Alpha-adrenergic Responsiveness Research Articles

Динамика изменения альфа-адренореактивности артерий тонкого кишечника при незавершенной и завершенной холодовой адаптации

Динамика изменения альфа-адренореактивности артерий тонкого кишечника при незавершенной и завершенной холодовой адаптации

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p<0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p<0.05), while female CCI rats had significant antinociception from WB4101 (p<0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.

Adrenergic hyperactivity: a missing link between multiple sclerosis and cardiovascular comorbidities?

The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, α-BRSa and β-BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, α-BRSa, β-BRSa and resting catecholamine levels. pwMS had higher α-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and β-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [χ2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between α-BRSa and upright systolic BP (rp =0.194, p = 0.017), α-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk.

AUTONOMIC DYSREGULATION IN PRIMARY HYPERTENSION

Objective: Introduction: Would cardiovascular autonomic reflexes help in understanding the diagnosis and the management of primary hypertension (PHT). The purpose of this study was to evaluate the cardiovascular autonomic reflexes in patients with primary hypertension (PHT), including masked hypertension (MHT), hypertension with type 2 diabetes (DHT), orthostatic hypertension (OHT) and orthostatic hypotension (OHypoT). Design and method: Patients and Methods. This prospective study included two groups: normotensive group, NT (N = 120) and primary hypertensive group, PHT (N = 120). The PHT group was divided in different subgroup: N1 = subgroup of MHT, N2 = subgroup of DHT, N3 = subgroup of OHT and N4 = subgroup of OHypoT. The PHT group as well as the subgroups were compared to NT group. The cardiovascular autonomic tests performed in these groups, included deep breathing (DB), hand-grip (Hg), mental stress (MS) and orthostatic (Orth) tests. Statistical analysis was done using the Student's t-test. Results: Results. Cardiovascular autonomic reflexes responses were as follows: Compared to NT, 1. Central alpha adrenergic response to mental stress test was of 20,0 ± 9,8% vs 15,2 ± 8,6% (p < 0,001) in PHT; 24,7 ± 7,2% vs 15,2 ± 4,5% (p < 0,001) in MHT; and 23,48 ± 9,82% vs 20,28 ± 9,60%(p = 0,243) in DHT. 2. Peripheral alpha adrenergic response to hand grip test of 16,7 ± 7,5% vs 13,3 ± 6,5% (p < 0,001) in PHT; 27,0 ± 5,4% vs 16,4 ± 4,5% (P < 0,001) in MHT; and 20,03 ± 8,05 vs 21,71 ± 11,23% (p = 0,588) in DHT. 3. Vagal response to deep breathing test was of 30,2 ± 8,1% vs 46,1 ± 2,1% (p < 0,001) in PHT; 30,5 ± 10,4% vs 32,7 ± 11,3% (p = 0,1) in MHT; and 23,09 ± 11,06% vs 34,15 ± 17,7% (p < 0,001) in DHT. Of interest orthostatic test showed that 70% of PHT had orthostatic hypertension and 15% orthostatic hypotension. Conclusions: Conclusion. PHT, hypertensive with type 2 diabetes, MHT have a significantly higher sympathetic response when compared to controls and vagal response significantly lower. The latter is accentuated by the association of diabetes to hypertension. The results attest that cardiovascular autonomic reflexes study is of high interest in assessing PHT

P320 Differences in adrenergic components of baroreflex response to Valsalva maneuver in patients with multiple sclerosis and healthy subjects

Objectives To evaluate differences in recently developed, non-standard adrenergic baroreflex sensitivity (BRS) indices between patients with multiple sclerosis (MS) and healthy controls (HC). Methods This retrospective analysis included 153 patients with MS and 20 healthy controls. Systolic blood pressure (sBP) responses during Valsalva maneuver (VM) were divided into three subtypes: balanced – type 1 (a sBP dip below baseline in late phase II (IIL) and recovery in phase IV), suppressed – type 2 (a non-dipping BP) and augmented – type 3 (a BP recovery in phase IIL) autonomic response. Alternative adrenergic component of BRS (BRSa1), and alpha- ( α -BRSa) and beta-adrenergic ( β -BRSa) components of adrenergic BRS were calculated and compared between the groups. For a subset of 103 MS patients, data on epinephrine, norepinephrine and dopamine immediately prior to performing Valsalva maneuver were available for analysis. Results There was no difference in the subtypes of sBP responses during VM between groups. Patients with MS had significantly higher α -BRSa compared to HC (6.36 ± 2.44 vs. 5.02 ± 2.14, p = 0.02). No differences were found for BRSa1 and β -BRSa. When we looked at differences in all three parameters depending on subtypes of sBP responses during VM, significant difference in α -BRSa was maintained only for the subtype 3 (7.27 ± 2.05 vs. 5.88 ± 2.09, p = 0.045). We found positive correlation between epinephrine and BRSa1 (rs 0.226, p = 0.04), negative correlation epinephrine and β -BRSa (rs −0.195, p = 0.050) and positive correlation between norepinephrine and α -BRSa (rs 0.228, p = 0.021). Discussion It has been suggested that new BRSa measurements may help differentiate normal physiologic variants from mild dysautonomia. Conclusion Healthy subjects and MS patients exhibit different alpha-adrenergic response to Valsalva maneuver. Significance A significant correlation between blood catecholamines and alfa and beta adrenergic response to Valsalva maneuver was observed.

P319 Differences in adrenergic components of baroreflex response to valsalva maneuver in patients with postural tachycardia syndrome and healthy subjects

Objectives To evaluate differences in recently developed, non-standard adrenergic baroreflex sensitivity (BRS) indices between patients with postural tachycardia syndrome (PoTS) and healthy controls (HC). Methods Criteria for diagnosing PoTS were increment of heart rate (HR) ⩾ 30 bpm or raise of HR to ⩾ 120 bpm in the absence of orthostatic hypotension, and a history of orthostatic intolerance symptoms lasting at least 3 months. PoTS patients were further divided into hyperadrenergic (H) and non-hyperadrenergic (NH) group according to standing serum NA ⩾ 3.5 nmol/L cut-off criteria. Eighteen PoTS patients and 19 HC performed tilt-up test and Valsalva maneuver. Alternative adrenergic component of BRS (BRSa1), and alpha- ( α -BRSa) and beta-adrenergic ( β -BRSa) components of adrenergic BRS were calculated and compared between the groups. Results PoTS group had significantly higher α -BRSa compared to HC (6.97 ± 2.39 vs. 5.13 ± 2.14, p = 0.02). No differences between PoTS patients and HC were found for BRSa1 (34.29 ± 21.79 vs. 32.41 ± 28.52, p = 0.823), and β -BRSa (1.43 ± 0.69 vs. 1.54 ± 1.19, p = 0.714). When comparing NH PoTS (N = 13), and H PoTS patients (N = 5) no significant differences were found in any of studied indices, although NH patients had slightly higher BRSa1 index than H patients (39.22 ± 23.06 vs. 21.46 ± 11.73, p = 0.055). Discussion High percentage of PoTSis caused by distal peripheral sympathetic dysfunction resulting in inadequate vasoconstriction in lower extremities. Higher α -BRSa found in PoTS patients may reflect an exaggerated vasoconstrictive response attempt following hemodynamic stress. Conclusion Healthy subjects and PoTS patients exhibit different alpha-adrenergic response to Valsalva maneuver. Significance Adrenergic indices may be a useful tool in studying pathophysiological differences in autonomic dysfunctions.

Sulphydryl oxidation restores alpha-adrenergic vascular response and improves survival in septic rats

Sulphydryl oxidation restores alpha-adrenergic vascular response and improves survival in septic rats

Cardiovascular autonomic response to amlodipine in primary hypertension.

Sympathetic hyperactivity may be involved in primary hypertension. The purpose of this study was to evaluate both sympathetic and vagal activity responses in patients receiving amlodipine as antihypertensive agent. Patients and Methods. This prospective study included a group of primary hypertensive patients (N = 32, mean age 54.6 ± 7.6 years). The cardiovascular autonomic tests performed in this group, before and after 3 months of daily oral administration of amlodipine, included deep breathing, hand-grip, and mental stress tests. Statistical analysis was done using the Student's t-test. Results. Cardiovascular autonomic reflexes responses before and after 3 months of amlodipine oral administration were as follows: the mental stress test stimulation method produced a central alpha adrenergic response of 23.9 ± 8.7% versus 11.2 ± 2.0% (P < 0.05), a central beta sympathetic response of 16.7 ± 9.2% versus 10.4 ± 1.3% (P < 0.05), a blood pressure increase in response to hand grip test of 20.5 ± 7.3% versus 10.7 ± 2.4% (P < 0.05), vagal response to deep breathing test was 21.2 ± 6.5% versus 30.8 ± 2.9%, (P < 0.05). Conclusion. The results attest that amlodipine may have an anti-sympathetic effect.

Protein Phosphatase 1b in the Solitary Tract Nucleus is Necessary for Normal Baroreflex Function

Despite positive metabolic effects, genetic deletion of protein phosphatase 1b (PTP1b) results in sympathetically mediated elevations in arterial pressure (AP) in mice. Because several PTP1b-regulated peptides also impair the baroreflex sensitivity (BRS) for control of heart rate (HR), we hypothesized that PTP1b in the solitary tract nucleus (NTS) participates in the maintenance of resting baroreflex function. To test this hypothesis, we performed acute bilateral microinjection of an allosteric PTP1b inhibitor (100 nM/120 nL) in the NTS of urethane/chloralose anesthetized Sprague-Dawley rats and assessed the BRS, responses to cardiac vagal chemosensitive fiber activation, and resting AP and HR before and after the injection. PTP1b inhibition impaired the BRS for bradycardia (n = 6; 0.93 ± 0.14 baseline vs. 0.48 ± 0.04 at 10 minutes vs. 0.49 ± 0.04 millisecond/mm Hg at 60 minutes; P < 0.01), with no significant effect on the BRS for tachycardia (0.30 ± 0.16 baseline vs. 0.24 ± 0.08 at 10 minutes vs. 0.24 ± 0.12 millisecond/mm Hg at 60 minutes). The reduced BRS for bradycardia was associated with a significant decrease in alpha-adrenergic responsiveness to phenylephrine at 60 minutes after PTP1b inhibition. Injection of the PTP1b inhibitor in the NTS elicited transient decreases in AP and HR in these animals. However, there was no effect of the inhibitor on depressor or bradycardic responses elicited by activation of cardiac vagal chemosensitive fibers, which converge with baroreceptor afferents in the NTS. These results suggest that PTP1b within the NTS may be a novel molecular mechanism for preservation of resting baroreflex function and provides further evidence for deleterious cardiovascular effects associated with PTP1b inhibition.

Similarities and differences in the effect of cocaine on α-adrenergic and muscarinic response

Similarities and differences in the effect of cocaine on alpha-adrenergic and muscarinic receptors were shown in three experimental models. The postsynaptic stimulating effect of cocaine through activation of alpha-adrenergic receptors was found in a chicken embryo without innervation and in an innervated rat vas deferens. Cocaine caused an increase of the amount of activated alpha-adrenergic receptors and the appearance of an additional receptor pool and changed their dimerization level. Cocaine acts as an antagonist on muscarinic receptors of the chicken embryo. The inhibition of muscarinic receptors in the rat brain by cocaine leads to a decrease in the number of receptors and their partial monomerization. Thus, cocaine influences both the alpha-adrenergic response and the muscarinic response by its influence on receptors. Experiments on various objects have shown that cocaine activates the alpha-adrenergic response and inhibits the muscarinic response.

Functional adaptation of venous smooth muscle response to vasoconstriction in proximal, distal, and varix segments of varicose veins

Varicose veins (VarVs) are a common disorder of venous dilation and tortuosity with unclear mechanism. The functional integrity and the ability of various regions of the VarVs to constrict is unclear. This study tested the hypothesis that the different degrees of venodilation in different VarV regions reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the postreceptor signaling mechanisms of vasoconstriction. Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control great saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass grafting. Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and changes in isometric constriction in response to angiotensin II (AngII, 10(-11)-10(-7) M), phenylephrine (PHE, 10(-9)-10(-4) M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT(1)R) was measured in vein tissue homogenate. AngII caused concentration-dependent constriction in control vein (max 35.3 +/- 9.6 mg/mg tissue, pED(50) 8.48 +/- 0.34). AngII caused less contraction and was less potent in proximal (max 7.9 +/- 2.5, pED(50) 6.85 +/- 0.61), distal (max 5.7 +/- 1.2, pED(50) 6.74 +/- 0.68), and varix segments of VarV (max 7.2 +/- 2.0, pED(50) 7.11 +/- 0.50), suggesting reduced AT(1)R-mediated contractile mechanisms. VarVs and control veins had similar amounts of AT(1)R. alpha-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0 +/- 13.9 mg/mg tissue, pED(50) 5.48 +/- 0.12) exceeding that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments but produced less constriction and was less potent in proximal segments of VarVs (max 32.1 +/- 6.4 mg/mg tissue, pED(50) 4.89 +/- 0.13) vs control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca(2+)-dependent response, produced significant constriction in control veins and similar contractile response in proximal, distal, and varix VarV segments, indicating tissue viability and intact Ca(2+)-dependent contraction mechanisms. Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may be involved in the progressive dilation in VarVs. Postreceptor Ca(2+)-dependent contraction mechanisms remain functional in VarVs. The maintained alpha-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.

Alpha-adrenergic responsiveness in rat isolated perfused heart after abdominal aortic coarctation.

Chronic isoproterenol pre-treatment, a well-known model of compensatory hypertrophy associated with cardiac beta-adrenoceptor desensitization, enhances the inotropic response to phenylephrine in rat isolated perfused hearts, supporting the hypothesis that myocardial alpha-adrenoceptor stimulation contributes to the maintenance of myocardial performance in situations in which cardiac beta-adrenoceptor function is compromised. To further corroborate this hypothesis, the effects of abdominal aortic coarctation on cardiac alpha-adrenergic responsiveness were investigated in Langendorff heart preparations. Abdominal aortic coarctation causes cardiac hypertrophy (21%) as shown by a significant increase in the ratio of ventricular dry weight to bodyweight. In preparations from hypertrophied rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 21- and 2-fold, respectively). However, the positive inotropic response to phenylephrine (10(-12) to 10(-4) M) remained unaffected following abdominal aortic coarctation, when compared with sham-operated rats. In preparations from both groups, phenylephrine infusion did not induce significant changes in heart rate. These results show that although abdominal aortic stenosis induced desensitization of cardiac beta-adrenoceptors, it did not enhance cardiac alpha-adrenoceptor responsiveness. This suggests that such an enhancement depends on the experimental model used to induce cardiac hypertrophy associated with desensitization of cardiac beta-adrenoceptors.

Effects of long-term pretreatment with isoproterenol on inotropic responsiveness to alpha-adrenoceptor stimulation: study in isolated perfused rat hearts.

The effects of chronic pretreatment with isoproterenol (5 mg kg(-1)) daily for 10 days on cardiac alpha-adrenergic responsiveness in Langendorff heart preparations were investigated. Isoproterenol pretreatment caused cardiac hypertrophy (29%) as shown by a significant increase in the ratio of ventricular dry weight to body weight. In preparations from isoproterenol-pretreated rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 32- and 4-fold, respectively), while the positive inotropic response to phenylephrine (10(-12) to 10(-4) M) was significantly enhanced (the phenylephrine concentration producing 50% of the maximum positive inotropic effect was reduced almost 100-fold), compared with saline-pretreated rats. In preparations from both groups, phenylephrine infusion induced non-significant changes in heart rate and its positive inotropic response was reduced in the presence of propranolol (10(-7) M) in the perfusion medium. Even under beta-adrenoceptor blockade, the curve for the phenylephrine-induced positive inotropic effect remained shifted upward after isoproterenol pretreatment. Chronic isoproterenol pretreatment induces the expected cardiac beta-adrenoceptor desensitization while simultaneously enhancing the positive inotropic responsiveness to phenylephrine in Langendorff heart preparations. These findings support the hypothesis that cardiac alpha1-adrenoceptor stimulation may contribute to the maintenance of myocardial function under conditions in which beta-adrenoceptor function is compromised.

The Effect of a Reduced-Calorie Diet on alpha-2 Adrenergic Receptor Responsiveness in Abdominal Adipose Tissue in Obese Men During Exercise

AbstractThere is at present an imperfect understanding of the effect of diet on availability of inhibitory receptors in fat cells during exercise among obese men. *Objective:* The purpose of this study was to determine whether diet results in downregulation of alpha-2 adrenergic receptor ([alpha]~2-AR~) messenger RNA (mRNA), improving metabolism in exercise in obese men. *Design:* One group, pre-test, post-test design.*Measurements:* Subcutaneous abdominal adipose tissue was tested for physiologic response, such as changes in catecholamines and other markers of lipolysis measured during periods of exercise, before and after a 12-week diet. Plasma markers of lipolysis/antilipolytic activity (catecholamines [adrenaline and noradrenaline], NEFA, lactate, glucose, hematocrit, or insulin levels) were analyzed at four points in time in order to determine the effect of exercise on [alpha]~2-AR~ and [beta]-AR responsiveness to sympathetic stimulation.*Subjects:* Otherwise healthy 18 to 45 year old obese men (defined as a body mass index (BMI) over 33 kg/m^2^). *Results:* The 12-week reduced calorie diet did not result in improved metabolism. Instead, upregulation of alpha-2 adrenergic receptor ([alpha]~2-AR~) messenger RNA (mRNA) was observed. On average, [alpha]~2-AR~ mRNA levels (ratio of [alpha]~2-AR~ to cyclophilin) in subjects increased by 0.022-0.023 after the diet. The average differences in of [alpha]~2-AR~ mRNA and [beta]-AR mRNA measured before and after diet were both insignificant (M = 0.015) t(4) = -0.911; P &gt; 0.05; (M = 0.0139; t(4) = 0.077; P &gt; 0.05). *Conclusion:* The observed direction of change in [alpha]~2-AR~ mRNA levels, when viewed together with the stability of [beta]-AR mRNA levels, suggests that upregulation of [alpha]~2-AR~ rather than downregulation occurred. Downregulation would account for decreased lipolytic activity during exercise, future study is needed.

Differentiation of Benign and Malignant Pathology in the Head and Neck Using 3T Apparent Diffusion Coefficient Values: Early Experience

The purpose of this work was to study differences in apparent diffusion coefficient (ADC) values between benign and malignant head and neck lesions at 3T field strength imaging. Our study population in this retrospective study was derived from the patient population who had undergone routine neck 3T MR imaging (for clinical indications) from December 2005 to December 2006. There were 33 patients identified: 17 with benign and 16 with malignant pathologies. In all of the subjects, conventional MR imaging sequences were performed apart from diffusion-weighted sequences. The mean ADC values in the benign and malignant groups were compared using an unpaired t test with unequal variance with a P < 0.05 considered statistically significant. There was a statistically significant difference (P = .004) between the mean ADC values (in 10(-3) mm(2)/s) in the benign and malignant lesions (1.505 +/- 0.487; 95% confidence interval, 1.305-1.706, and 1.071 +/- 0.293; 95% confidence interval, 0.864-1.277, respectively). There were 2 malignant lesions with ADC values higher than 1.3 x 10(-3) mm(2)/s and 5 benign lesions with ADC values less than 1.3 x 10(-3) mm(2)/s. The lack of overlap of ADC values within 95% confidence limits suggests that a 3T ADC value of 1.3 x 10(-3) mm(2)/s may be the threshold value for differentiation between benign and malignant head and neck lesions. ADC values of benign and malignant neck pathologies are significantly different at 3T imaging, though larger studies are required to establish threshold ADC values that can applied in daily clinical practice.

Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: Role of augmented renal alpha-adrenergic responsiveness

The pathogenesis of cisplatin-induced renal failure is related to reduced renal blood flow due to severe tubular damage and enhanced renovascular resistance. It is also known that α 1-adrenoceptors, the major subtype of α-adrenoceptors in renal vasculature play the pivotal role in regulating renal hemodynamics. With this background, we have hypothesized that the altered renal hemodynamics and enhanced renovascular resistance in cisplatin-induced renal failure might be caused by the altered α-adrenergic responsiveness with a possible involvement of α 1-adrenoceptors in the renal vasculature. In a unique experimental approach with anesthetized rats, this study has therefore examined if there is any shift in the renovascular responsiveness to renal nerve stimulation and a series of α-adrenergic agonists in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats with cisplatin-induced renal failure in comparison with their body weight-matched normal controls. Thirty-two male rats of both WKY ( n=16) and SHR ( n=16) origin with body weight 236±7.9 g received cisplatin (5 mg/kg i.p.). The renal failure was confirmed in terms of significantly reduced renal blood flow, reduced creatinine clearance, increased fractional excretion of sodium, increased kidney index (all P<0.05) and tubular damage. After 7 days of cisplatin, the overnight fasted rats were anesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and renal vasoconstrictor experiments were done. The changes in the vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by electrical renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine and methoxamine. It was observed that in the cisplatin-treated renal failure WKY and SHR rats there were significant (all P<0.05) reductions in the renal blood flow along with significantly ( P<0.05) higher renal adrenergic responsiveness as compared with their non-renal failure controls. The data showed that in the renal failure WKY and SHR rats, the altered renal hemodynamics might be caused by an augmented renal adrenergic responsiveness. The results obtained further led us to suggest that the augmented renal adrenergic responsiveness in the cisplatin-induced renal failure rats were possibly mediated by the α 1-adrenoceptors.

Defective Adrenergic Responses in Patients With Arsenic-induced Peripheral Vascular Disease

Blackfoot disease is an endemic arsenic-induced peripheral vascular disease in southern Taiwan. The main pathologic feature is atherosclerosis, which may relate to imbalances of the adrenergic system. The purpose of this study is to investigate the peripheral adrenergic responses of patients with blackfoot disease. Eight patients with blackfoot disease and four age-matched healthy controls were enrolled in this study. Baseline cutaneous perfusion was measured with a laser Doppler flowmeter. The response of alpha-adrenoceptors in the cutaneous microcirculation was assessed with laser Doppler flowmetry with iontophoresis of phenylephrine into the nailfold. In vitro binding with (125)I-cyanopindolol determined beta-adrenoceptor density in lymphocytes. The cyclic adenosine monophosphate (cAMP) level at baseline and after isoproterenol stimulation reflects lymphocyte beta-adrenergic responsiveness. Results revealed persistently decreased skin perfusion in patients with blackfoot disease. In contrast, there was a transient decrease in skin perfusion in healthy controls after iontophoresis of phenylephrine. Both beta-2 receptor density and isoproterenol-stimulated cAMP levels in lymphocytes decreased. Increased peripheral alpha-adrenergic response and decreased beta-2-adrenergic response are related to increased vascular tone and result in atherosclerosis. Our findings of accentuated alpha-adrenergic response in microcirculation and decreased lymphocyte beta-2-adrenoceptor response play an important role in the pathogenesis of atherosclerosis in blackfoot disease.

Differential effects of losartan and candesartan on vasoconstrictor responses in the ratThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat.

Mechanisms of vasoconstriction with direct skin cooling in humans

direct skin cooling causes a vasoconstriction partly dependent on α2-adrenergic function. In in vitro studies, this is a manifestation of reactive oxygen species stimulating Rho and Rho kinase to cause translocation of α2C-receptors from the Golgi to the plasma membrane. In this issue of American

Differential alpha‐2 adrenergic functional response in juvenile versus adult rats treated with the tricyclic antidepressant desipramine

Adults respond well to antidepressant drugs acting on the noradrenergic system, .e.g., desipramine (DMI), but children generally do not. To determine if this differential response was correlated with an altered alpha-2 adrenergic functional response to DMI treatment, the hypothermic effect of the alpha-2 agonist, brimonidine was compared in juvenile (post-natal day 13) and adult rats. Rats were treated for four days with DMI with the dose given to the juveniles (6 mg/kg/day) adjusted to give brain concentrations comparable to those in adult rats (20 mg/kg/day). Brimonidine, an alpha-2 adrenergic receptor agonist, induced a hypothermic response in control rats at both age groups that could be blocked by the alpha-2 antagonist, RX821002. DMI treated adult, but not juvenile, rats demonstrated an enhanced hypothermic response (p < 0.002) when brimonidine was given at a time point where over 95% of the DMI had cleared from the brain. These results support the concept that children and juvenile rats do not respond well to tricyclic antidepressants because the mechanisms regulating the alpha-2 adrenergic receptor are not fully developed. Research supported by MH64772.