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Geoffrey A Head

Publications and source records attributed to Geoffrey A Head.

At least 19 recordsLinked to original sources
PubMed2007

Contribution of imidazoline receptors and alpha2-adrenoceptors in the rostral ventrolateral medulla to sympathetic baroreflex inhibition by systemic rilmenidine.

OBJECTIVES: To determine whether the hypotensive and sympathetic baroreflex inhibition by rilmenidine administered systemically are mediated via imidazoline receptors in the rostral ventrolateral medulla (RVLM). METHODS: Initial dose-response curves to rilmenidine were determined in urethane anaesthetized rabbits. Effects of a single intravenous dose of rilmenidine (445 microg/kg) on the renal sympathetic nerve activity (RSNA) baroreflex were examined before and after microinjection into the RVLM of the mixed imidazoline/alpha2-adrenoceptor antagonist idazoxan and the alpha2-adrenoceptor antagonist 2-methoxyidazoxan (2-MI). RESULTS: Intravenous administration of rilmenidine lowered mean arterial pressure and RSNA, inhibited the RSNA baroreflex range by 33% and shifted the baroreflex curve to the left. Idazoxan injected into the RVLM reversed the hypotension and completely restored the baroreflex curve at doses that did not affect the hypotension produced by the selective alpha2-adrenoceptor agonist alpha-methylnoradrenaline. The alpha2-adrenoceptor antagonist, 2-MI also reversed the rilmenidine sympatho-inhibition suggesting that alpha2-adrenoceptors are activated as well. CONCLUSIONS: The results of the present study show that the hypotensive and sympatho-inhibitory actions of systemic rilmenidine are primarily mediated via imidazoline receptors in the RVLM. However, alpha2-adrenoceptors are also involved, probably as a direct result of the imidazoline receptor action.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2006

Renin enhancer is critical for control of renin gene expression and cardiovascular function.

The important cardiovascular regulator renin contains a strong in vitro enhancer 2.7 kb upstream of its gene. Here we tested the in vivo role of the mouse Ren-1c enhancer. In renin-expressing As4.1 cells stably transfected with Ren-1c promoter with or without enhancer, expression of linked beta-geo reporter, stable expression, and colony formation were dependent on the presence of the enhancer. We then generated mice carrying a targeted deletion of the enhancer (REKO mice) and found marked depletion of renin in renal juxtaglomerular and submandibular ductal cells, as well as hyperplasia of macula densa cells. Plasma creatinine was increased, but electrolytes were normal. Male REKO mice implanted with telemetry devices had 9 +/- 1 mm Hg lower mean arterial pressure (p < 0.001), which was partly normalized by a high NaCl diet. Locomotor activity was lower, and baroreflex sensitivity was normal. Markedly reduced mean arterial pressure variability in the midfrequency band indicated a contribution of reduced sympathetic vasomotor tone to the hypotension. In conclusion, the renin enhancer is critical for renin gene expression and physiological sequelae, including response to alteration in salt intake. The REKO mouse may be useful as a low renin expression model.

Animals↗
PubMed2006

Tempol in the dorsomedial hypothalamus attenuates the hypertensive response to stress in rabbits.

BACKGROUND: We have recently shown that microinjection of the superoxide dismutase mimetic tempol into the pressor region of the rostral ventrolateral medulla attenuates the cardiovascular response to mental (air-jet) stress in rabbits. In the present study, we examined the influence of tempol on the blood pressure (BP) and heart rate (HR) responses to stress in the key region of the hypothalamic defense area, the dorsomedial hypothalamus (DMH). METHODS: New Zealand White rabbits were implanted with guide cannulae for microinjection into the DMH. After 2 weeks of recovery, the cardiovascular response to air-jet stress was evaluated before and after bilateral injections of equimolar doses (20 nmol) of the superoxide scavengers tempol, tiron, or 3-carbamoyl proxyl (3-CP). RESULTS: Microinjection of superoxide scavengers into the DMH did not alter resting BP or HR. Air-jet stress evoked a sustained increase in BP (+16 +/- 2 mm Hg) and HR (+48 +/- 5 beats/min). Tempol attenuated the pressor and tachycardic responses to air-jet stress by 39% +/- 10% and 37% +/- 8%, respectively (P < .05), without altering stress-induced tachypnea. Similarly, tiron selectively decreased the BP and HR responses to stress by 33% +/- 8% and 53% +/- 13%, respectively (P < .05). Conversely, 3-CP, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the cardiovascular stress response, and neither did vehicle. Microinjection of tempol or tiron just outside the DMH had little effect on stress responses. CONCLUSIONS: This study provides first published evidence that superoxide in the DMH is important in the regulation of acute hypertensive and tachycardic responses to mental stress.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2006

Rate of morning increase in blood pressure is elevated in hypertensives.

BACKGROUND: We applied a new logistic curve fitting procedure to ambulatory blood pressure (ABP) recordings to determine whether the rate of increase in systolic (SBP), mean (MBP) and diastolic blood pressure (DBP) and heart rate (HR) in the morning is related to the level of BP in subjects. METHODS: The rate of transition in the morning and evening period was determined using a six-parameter double-logistic equation applied to 528 ABP recordings from a cardiovascular risk assessment clinic. Based on daytime BP (MBP, SBP, or DBP), the upper quartile (UQ, n = 132) and lower quartile (LQ) were compared. RESULTS: Subjects in the UQ of daytime MBP were hypertensive and showed greater day-night differences compared to normotensive subjects in the LQ (29 +/- 1 mm Hg for MBP compared to 20 +/- 1 mm Hg). The rate of morning increase in SBP and DBP was 42% and 30% greater in UQ subjects compared to the LQ subjects (P < .05). The rates of evening decrease in all BPs were 69% to 84% greater in the subjects in the UQ. Similar results were obtained if subjects were divided according to daytime SBP or DBP. The rate of morning increase in MBP was correlated with daytime BP, but not night-time or 24 h MBP. CONCLUSIONS: The rate of morning increase in BP is greater in those subjects with the highest daytime BP. The exaggerated rate of morning increase in BP in this group, which were all hypertensive, may also be important for greater cardiovascular risk.

Blood Pressure↗
PubMed2005

Angiotensin II in dorsomedial hypothalamus modulates cardiovascular arousal caused by stress but not feeding in rabbits.

The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA(A) agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56-63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT(1)-receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.

Angiotensin II↗
PubMed2004

Nonsymmetrical double logistic analysis of ambulatory blood pressure recordings.

We developed an asymmetric double logistic curve-fitting procedure for circadian analysis that can determine the rate of change in variables during the day-to-night separately from the night-to-day transition for use in animal studies. We now have applied this procedure to 24-h systolic (SAP) and diastolic arterial pressure (DAP) and heart rate ambulatory recordings from 302 patients. In 292 cases, all parameters showed a pattern of higher day and lower night values. In men there was a similar rate of transition between day and night or from night to day for both SAP and DAP that lasted 3-4 h, indicating a symmetrical diurnal pattern. By contrast, women showed a faster rate of decrease in mean arterial pressure in the evening compared with men (P < 0.05) and therefore showed an asymmetric diurnal SAP pattern. For both men and women, there was a markedly greater rate of morning increase in heart rate compared with the rate of evening decrease (2.2- and 1.9-fold, respectively, P < 0.001). The logistic method provided a better fit than the square-wave or the cosinor method (P < 0.001) and more appropriately detected nondippers. We conclude that analysis of ambulatory recordings by a new logistic curve-fitting method reveals more rapid reductions in evening SAP in women than men but both have two- to threefold more rapid morning rates of tachycardia. The ability of the double logistic method to determine the diurnal blood pressure rates of change independently is key to determining new markers for cardiovascular risk.

Adult↗
PubMed2004

Aromatase-deficient (ArKO) mice have reduced blood pressure and baroreflex sensitivity.

Aromatase-deficient (ArKO) mice are deficient in estrogens due to deletion of the aromatase gene. We hypothesized that there may be changes in the cardiovascular system of ArKO mice because of evidence linking estrogens with improved cardiovascular outcomes and the induction of the glucocorticoid-metabolizing enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), gene in the kidney, which is important for the regulation of blood pressure (BP). BP and baroreflex sensitivity (BRS) in female conscious ArKO mice were compared with those in age- and weight-matched wild-type (WT) mice. Power spectral analysis was used to determine cardiovascular variability and BRS. Although systolic BP was similar in the two groups, diastolic and mean BPs were lower in the ArKO mice (-6.3 +/- 1.9 and -4.6 +/- 2.1 mm Hg, respectively). Heart rate (HR) was greater in the ArKO mice (+36 +/- 6 beats/min). The mean BP in WT mice was 105 mm Hg, and the HR was 481 beats/min. In the autonomic frequency range, BP variability was 74% greater, and HR variability was only 26% that in WT mice. The BRS of ArKO mice was 46% of the value observed in WT mice. 11betaHSD2 levels were unaltered in ArKO mice, except in the kidney, where they were only 10% of WT levels. Estradiol administration to ArKO mice restored renal 11betaHSD2 to WT levels. The results show that ArKO mice have lower diastolic BP, but increased BP variability, perhaps due to an impaired BRS. Thus, aromatase activity is critical for normal autonomic control of the heart and, hence, for reducing the deleterious effects of high BP variability.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress.

Superoxide has been shown to be an important intracellular mediator of actions of angiotensin II. Recently, we found that blockade of angiotensin II type-1 receptors in the rostral ventrolateral medulla (RVLM) abrogated the pressor effect of emotional stress in rabbits. In the present study, we examined the influence of superoxide dismutase mimetics, tempol and tiron, in RVLM on cardiovascular stress response in conscious rabbits. Air-jet stress evoked a sustained increase in blood pressure (+14+/-2 mm Hg), tachycardia (+52+/-7 bpm), and renal sympathoactivation (+58+/-8%). Bilateral microinjections of tempol or tiron (20 nmol) into RVLM did not alter resting cardiovascular parameters, but attenuated the pressor, sympathetic, and tachycardiac response to stress by 40% to 55%. By contrast, 3-carbamoylproxyl, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the stress response. Neither tempol nor tiron altered the sympathoexcitatory response to glutamate microinjections into RVLM or to baroreceptor unloading. Microinjections of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 10 nmol) into RVLM did not affect the stress response. Coinjections of tempol and L-NAME decreased the pressor response to stress by 35+/-3%. Tempol attenuated the pressor response to microinjection of angiotensin II into RVLM by 59+/-15%, whereas L-NAME did not alter this response. These results suggest that superoxide dismutase mimetics in RVLM attenuate, partially via a nitric oxide-independent mechanism, the pressor effect of emotional stress in rabbits. Together with our previous studies, these results also indicate that superoxide is a key mediator of excitatory actions of angiotensin II in RVLM during acute stress.

Angiotensin II↗
PubMed2004

Sympathetic responses to stress and rilmenidine in 2K1C rabbits: evidence of enhanced nonvascular effector mechanism.

We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced "nonvascular" neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension.

Animals↗
PubMed2004

Non-symmetrical double-logistic analysis of 24-h blood pressure recordings in normotensive and hypertensive rats.

OBJECTIVE: To determine the suitability of a new logistic curve fitting procedure to measure the diurnal rates of transition from the active to the asleep periods separately. METHOD: We applied this method to 24-h telemetry recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively), heart rate (HR) and locomotor activity of normotensive Sprague-Dawley rats (SDR) and spontaneously hypertensive rats (SHR). RESULTS: There was a similar pattern of higher awake and lower sleep values (16 +/- 1 mmHg SAP, 77 +/- 2 bpm HR and 40 +/- 2 units activity) in SHR. In SDR, awake-asleep differences were less for SAP (9 +/- 1 mmHg) but similar for HR (83 +/- 2 bpm). In SHR, while the blood pressure patterns were symmetrical, the rate of rise in activity and HR during arousal was more rapid than the rate of decline during the dark to light transition. By contrast in SDR, the arousal rate of increase in blood pressure and HR was much less than the rate of decline. Thus SHR have an exaggerated arousal surge in DAP compared with SDR. Double logistic provides a better fit than Cosinor or square wave and better estimates of day-night differences than partial Fourier. CONCLUSIONS: Analysis of 24-h recordings by a new logistic curve method reveals distinct asymmetric circadian patterns of cardiovascular and activity changes in rats. The greater surge in arousal blood pressure in SHR is not associated with differences in HR or activity changes and may be inherent to the underlying mechanisms contributing to the hypertension in SHR.

Animals↗
PubMed2003

The rostral ventrolateral medulla mediates sympathetic baroreflex responses to intraventricular angiotensin II in rabbits.

The present study examined the role of the rostral ventrolateral medulla (RVLM) in mediating the pressor and renal sympathetic baroreflex effects of intraventricularly administered angiotensin II (Ang II) in urethane anaesthetised rabbits. Microinjection of Ang II over a wide range of medullary sites showed that pressor responses were observed only in the RVLM. Ang II was particularly potent in producing a transient pressor response at this site with a half maximal dose of 9 fmol. The administration of the Ang II antagonist Sar(1)-Ile(8)-Ang II (10 pmol) bilaterally into the RVLM inhibited the pressor response to local and fourth ventricular Ang II, but not the pressor response to RVLM applied glutamate. To determine the contribution of the RVLM to the renal sympathetic baroreflex effects of Ang II, blood pressure-renal sympathetic nerve activity (RSNA) curves were constructed with intravenous infusion of phenylephrine or nitroprusside before and after Ang II, vehicle or glutamate infusions into the RVLM. Ang II infusion of 4 pmol/min into the RVLM increased blood pressure by 8+/-3 mm Hg and shifted the renal sympathetic baroreflex curve to the right. The maximum RSNA evoked by lowering blood pressure increased by 36+/-6%, similar to the effect seen with fourth ventricular Ang II and RVLM glutamate. These studies suggest that the major medullary pressor site of action of Ang II when injected into the hindbrain cerebro-spinal fluid of anaesthetized rabbits is the RVLM where it facilitates baroreflex control of RSNA.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2003

Method for in vivo calibration of renal sympathetic nerve activity in rabbits.

A major difficulty of recording from peripheral sympathetic nerves is that microvolt values reflect characteristics of the recording conditions and limit comparisons between different experimental groups. In this study we assessed methods of calibrating renal sympathetic nerve activity (RSNA) in conscious rabbits. Calibration values were obtained from maximum RSNA responses to nasopharyngeal stimulation, airjet stress or unloading baroreceptors. Curves relating RSNA to blood pressure were produced by raising and lowering blood pressure with vasoactive drugs. To assess whether normalization would eliminate differences between RSNA curves which were most likely due to recording conditions, rabbits were first divided into two groups with high or low basal microvolt levels of RSNA, then again into two groups with high or low heart rate. In both cases, curves were similar if values were normalized by nasopharyngeal stimulation or by the upper plateau value. In hypertensive rabbits, where the baroreflex is suppressed, only the nasopharyngeal method showed this attenuated pattern. This method also eliminated the 50% decay in basal RSNA measured over 5 weeks. We conclude that expressing RSNA in terms of the maximum response to nasopharyngeal stimulation provides a calibration method suitable for comparing nerve activity over the long term as well as showing valid differences in baroreflex curves between different experimental groups.

Adrenergic Fibers↗
PubMed2003

AT1 receptors in the RVLM mediate pressor responses to emotional stress in rabbits.

In this study, we examined the role of angiotensin type 1 (AT1) receptors in the rostral ventrolateral medulla (RVLM) in mediating the pressor action of emotional stress in conscious rabbits. Rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the RVLM and an electrode for measuring renal sympathetic nerve activity (RSNA). Airjet stress evoked increases in arterial pressure, heart rate, and RSNA, which reached a maximum (+9+/-1 mm Hg, +20+/-5 beats/min, and +93+/-17%, respectively) in the first 2 minutes of stress exposure. Then RSNA rapidly returned to prestress values, while arterial pressure and heart rate remained close to the maximal level until the conclusion of the 7-minute airjet exposure. Microinjections of the nonselective angiotensin receptor antagonist sarile (0.5 nmol, n=8) or AT1 receptor antagonists losartan (2 nmol, n=6) or candesartan (0.2 nmol, n=6) into the RVLM did not alter resting cardiovascular parameters. By contrast, the antagonists attenuated the sustained phase (4 to 7 minutes) of the pressor stress response by 55% to 89%. However, only sarile decreased the onset of this response. The antagonists affected neither the stress-induced tachycardia nor the pressor response to glutamate microinjections. Microinfusion of angiotensin II (4 pmol/min, n=8) into the RVLM did not change the pressor response to airjet stress but attenuated tachycardic response by 47%. Microinjections of vehicle did not alter the cardiovascular stress response. Sarile, losartan, and angiotensin II did not affect the sympathoexcitatory response to baroreceptor unloading. These results suggest that AT1 receptors in the RVLM are important in mediating the pressor effects of emotional stress in conscious rabbits.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2003

Importance of imidazoline-preferring receptors in the cardiovascular actions of chronically administered moxonidine, rilmenidine and clonidine in conscious rabbits.

OBJECTIVE: To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine. DESIGN AND METHODS: In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade. RESULTS: Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2) CONCLUSIONS: The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2003

Are centrally acting imidazoline agents appropriate therapy for renovascular hypertension?

An increased role of the sympathetic nervous system has been suggested to be a major contributor to the chronic elevation of BP in renovascular hypertension. We assessed the effects of rilmenidine, a centrally acting antihypertensive imidazoline agent, on BP and renal sympathetic nerve activity (RSNA) in 2K1C renovascular hypertensive conscious rabbits. Rabbits were made hypertensive with a renal clip or were sham-operated and were studied 3 and 6 weeks later. Acute treatment with rilmenidine reduced BP to a greater extent in the hypertensive rabbits. Although rilmenidine reduced the heart rate by the same extent in all groups, rilmenidine produced much less inhibition of RSNA in the hypertensive animals. These studies suggest that the contribution of the sympathetic nervous system is greater in 2K1C hypertension and that imidazoline agents may be beneficial in treating renovascular hypertension.

Animals↗