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PubMed1994

Inhibition of alpha 2-adrenergic vasoconstriction during contraction of glycolytic, not oxidative, rat hindlimb muscle.

Previous studies have produced conflicting evidence as to whether sympathetic vasoconstriction is impaired in active skeletal muscle. Because alpha 2-, not alpha 1-, adrenergic vasoconstriction is attenuated by mild acidosis, we hypothesized that alpha 2-mediated sympathetic vasoconstriction would be attenuated in contracting glycolytic muscle, which produces more acidosis than oxidative muscle. We compared effects of lumbar sympathetic nerve stimulation and alpha-adrenergic agonists on arterial pressure, femoral blood flow, and force output during contractions of oxidative or glycolytic muscles in anesthetized rats. We found that 1) sympathetic vasoconstriction was preserved during contractions of oxidative soleus muscle and during low-intensity contractions of glycolytic gastrocnemiusplantaris muscles but was abolished during maximal contractions of these glycolytic muscles; 2) this sympatholytic effect was caused by impaired alpha 2-, not alpha 1-, vasoconstriction; and 3) the increased muscle blood flow resulting from a combination of impaired vasconstriction and increased arterial pressure was paralleled by increased force of gastrocnemius-plantaris muscle contraction. Thus contraction-induced impairment of alpha 2-vasoconstriction can augment muscle blood flow and muscle contraction, but the degree of impairment depends on fiber type and intensity of muscle contraction.

Adrenergic alpha-Agonists↗
PubMed1989

Effects of fentanyl on carotid sinus baroreflex control of circulation in rabbits.

The effects of intravenous administration of fentanyl on carotid sinus baroreflex control of hemodynamics were investigated in chronically instrumented rabbits. Carotid sinus baroreflex was assessed by bilateral carotid occlusion (BCO), and the responses of mean arterial pressure (MAP), heart rate (HR), mean ascending aortic flow (MAF), and total peripheral resistance (TPR) were obtained. Hemodynamic responses to BCO were examined with cumulative doses of 5, 10, and 15 micrograms/kg of fentanyl. Fentanyl did not affect MAP and TPR but reduced HR and MAF dose dependently. Fentanyl did not attenuate the MAP response to BCO significantly. In contrast, fentanyl significantly attenuated the TPR response from 0.126 +/- 0.003 to 0.104 +/- 0.005 mmHg.min-1.ml-1 and augmented the HR response from 31 +/- 2 to 47 +/- 3 beats/min in the conscious state and at 15 micrograms/kg of fentanyl, respectively. The administration of atropine after the fentanyl attenuated MAP and HR responses to 79.9 and 27.7% of those of 10 micrograms/kg of fentanyl, respectively. We suggest that these dissociated hemodynamic responses reflect the vagotonic and sympatholytic effects of fentanyl on the baroreflex pathways.

Animals↗
PubMed1996

Activation of GABAB receptors increases a potassium conductance in rat bulbospinal neurons of the C1 area.

In anesthetized rats, iontophoresis of the gamma-aminobutyric acid (GABAB)-receptor agonist and antispastic drug baclofen inhibits the bulbospinal vasomotor neurons of the rostral ventrolateral medulla (RVLM). The present study was carried out to determine whether C1 adrenergic and other bulbospinal neurons of the RVLM have postsynaptic GABAB receptors. Retrogradely labeled RVLM bulbospinal neurons (n = 52) were recorded in 120-micron-thick slices from neonatal rat brain (3-10 days old). Most neurons (48/52) were tonically active (3 +/- 0.6 spikes/s). Twenty-six neurons were recovered histologically, and 18 of them were immunoreactive for tyrosine hydroxylase (TH). In current clamp, baclofen (0.3-10 microM) hyperpolarized RVLM bulbospinal cells in a dose-dependent manner (16 +/- 0.5 mV hyperpolarization by 3 microM baclofen; n = 19) and decreased input resistance by 40% (n = 10). In voltage clamp (1 microM tetrodotoxin present; holding potential: -40 to -60 mV), 3 microM baclofen induced an outward current of 21 +/- 2 pA (n = 29). This current exhibited inward rectification and reversed polarity close to the K+ equilibrium potential (external K+ from 2.5 to 10 mM). The current induced by baclofen was reduced 90% by 0.1-0.2 mM BaCl2 (n = 6) and was blocked reversibly by the selective GABAB-receptor antagonist CGP-55845A (0.5-1 microM; n = 6). All histologically verified TH-immunoreactive cells (n = 18) were sensitive to baclofen. In summary, RVLM bulbospinal neurons including C1 adrenergic cells possess GABAB receptors. Activation of these receptors increases an inwardly rectifying K+ conductance. This effect reduces the intrinsic firing frequency of RVLM vasomotor neurons "in vitro" and may contribute to the sympatholytic action of baclofen "in vivo."

Action Potentials↗
PubMed1997

Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?

Clonidine and related alpha 2-adrenergic receptor (alpha 2AR) agonists lower arterial pressure primarily by an action within the central nervous system. These drugs also have varying degrees of affinity for other cellular components called nonadrenergic imidazoline binding sites (NAIBS). For over 20 years, the alpha 2AR agonist activity of clonidine-like drugs was thought to account for their therapeutic effects (alpha 2 theory). However, several groups have recently proposed a competing "imidazoline theory" according to which the hypotensive effect of clonidine-like drugs would in fact owe more to their affinity for one type of NAIBS, called I1 receptors. The alpha 2-theory is strongly supported by four main types of congruent data. First, the hypotensive effect of systemically administered clonidine is blocked by alpha 2AR antagonists that are without affinity for I1 NAIBs. Second, the hypotensive effect of intravenous clonidine is absent in genetically engineered mice in which a defective alpha 2AAR has been substituted for the normal one. Third, the sympatholytic effect of clonidine is consistent with the presence of conventional inhibitory alpha 2ARs on sympathetic preganglionic neurons and on their main excitatory inputs in the medulla oblongata. Fourth, the first I1 ligand without affinity for alpha 2ARs was found to be biologically inactive. The imidazoline theory is supported by a limited repertoire of whole animal "in vivo" pharmacological experiments that remain open to a wide range of interpretations. In conclusion, the bulk of the evidence strongly supports a largely predominant role of alpha 2AR mechanisms in the action of most clonidine-like agents at therapeutically relevant doses or concentrations. Even the small pharmacological differences between these agents cannot yet be linked with certainty to their relative affinity for I1 NAIBS.

Adrenergic alpha-Agonists↗
PubMed2002

Sympathetic modulation of renal blood flow by rilmenidine and captopril: central vs. peripheral effects.

Renal blood flow (RBF) is modulated by renal sympathetic nerve activity (RSNA). However, agents that are supposed to reduce sympathetic tone, such as rilmenidine and captopril, influence RBF also by direct arteriolar effects. The present study was designed to test to what extent the renal nerves contribute to the renal hemodynamic response to rilmenidine and captopril. We used a technique that allows simultaneous recording of RBF and RSNA to the same kidney in conscious rabbits. We compared the dose-dependent effects of rilmenidine (0.01-1 mg/kg) and captopril (0.03-3 mg/kg) on RBF and RSNA in intact and renal denervated (RNX) rabbits. Because rilmenidine and captopril lower blood pressure, studies were also performed in sinoaortically denervated (SAD) rabbits to determine the role of the baroreflex in the renal hemodynamic response. Rilmenidine reduced arterial pressure, RBF, and RSNA dose dependently. In intact rabbits (n = 10), renal conductance (RC) remained unaltered (3 +/- 5%), even after the 1-mg/kg dose, which completely abolished RSNA. In RNX rabbits (n = 6), RC fell by 18 +/- 5%, whereas in SAD rabbits (n = 7) RC increased by 30 +/- 20% after rilmenidine. In intact rabbits, captopril increased RSNA maximally by 64 +/- 8%. RSNA did not rise in SAD rabbits. Despite the differential response or absence of RSNA, captopril increased RC to a comparable degree (maximally 40-50%) in all three groups. Using spectral analysis techniques, we found that in all groups, independently of ongoing RSNA, captopril, but not rilmenidine, attenuated both myogenic (0.07-0.25 Hz) and tubuloglomerular feedback (0.01-0.07 Hz) related fluctuations in RC. We conclude that, in conscious rabbits, the renal vasodilator effect of rilmenidine depends on the level of ongoing RSNA. Its sympatholytic effect is, however, blunted by a direct arteriolar vasoconstrictor effect. In contrast, the renal vasodilator effect of captopril is not modulated by ongoing RSNA and is associated with impairment of autoregulation of RBF.

Animals↗
PubMed1999

The antihypertensive effect of the berberine derivative 6-protoberberine in spontaneously hypertensive rats.

Berberine is a natural isoquinoline alkaloid found in plants of the Ranunculaceae and Berberidaceae families. Extracts from berberine-containing plants have been used as traditional Chinese folk remedies for centuries. The antihypertensive effects of the berberine derivative 6-protoberberine (PTB-6) were studied in spontaneously hypertensive rats (SHRs). In conscious SHRs, PTB-6 lowered the systolic blood pressure in a dose-dependent manner (6-PTB: 5 mg/kg, -31.1 +/- 1.6 mm Hg; 10 mg/kg, -42.4 +/- 3.1 mm Hg). Cardiac output using the thermodilution method was reduced in PTB-6-treated anesthetized SHRs with a tendency to decrease in heart rate. Injection of PTB-6 into the intracerebral ventricles of SHRs lowered the systolic arterial blood pressure and heart rate. The berberine derivative PTB-6 is an effective antihypertensive agent. The mechanism of the antihypertensive effect of PTB-6 is probably through a central sympatholytic effect.

Animals↗
PubMed2002

Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on measures of nonlinearity and chaos of heart rate.

Depression is associated with increased cardiovascular mortality in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate variability (HRV) or heart period variability has been linked to sudden death in patients with cardiac disease as well as in normal controls. Recent studies have shown decreased vagal function in cardiac patients with depression as well as in depressed patients without cardiac illness. In this study, we compared 20 h awake and sleep heart period nonlinear measures using quantification of nonlinearity and chaos in two groups of patients with major depression and ischemic heart disease (mean age 59-60 years) before and after 6 weeks of treatment with paroxetine or nortriptyline. Patients received paroxetine, 20-30 mg/day or nortriptyline targeted to 190-570 nmol/l for 6 weeks. For HRV analysis, 24 patients were included in the paroxetine treatment study and 20 patients in the nortriptyline study who had at least 20000 s of awake data. The ages of these groups were 60.4 +/- 10.5 years for paroxetine and 60.8 +/- 13.4 years for nortriptyline. There was a significant decrease in the largest Lyapunov exponent (LLE) after treatment with nortriptyline but not paroxetine. There were also significant decreases in nonlinearity scores on S(netPR) and S(netGS) after nortriptyline, which may be due to a decrease in cardiac vagal modulation of HRV. S(netGS) and awake LLE were the most significant variables that contributed to the discrimination of postparoxetine and postnortriptyline groups even with the inclusion of time and frequency domain measures. These findings suggest that nortriptyline decreases the measures of chaos probably through its stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Nortriptyline was also associated with a significant decrease in nonlinearity scores, which may be due to anticholinergic and/or sympatholytic effects. As depression is associated with a strong risk factor for cardiovascular mortality, one should be careful about using any drug that adversely affects cardiac vagal function.

Aged↗
PubMed1978

Influence of structural changes in the imidazolidine ring of clonidine on hypotensive activity.

2-(2,6-Dichlorophenylimino)piperimidine with HNO3 (St-404), 2-(2,6-dichlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazole fumarate (compound 44-549) and 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline with HCl (TIQ) were studied with respect to their effects on blood pressure and heart rate in the anaesthetized, normotensive rat following intravenous administration and in the chloralose-anaesthetized cat by means of infusions via the left vertebral artery. St-404 and compound 44-549 possess central hypotensive and bradycardic activities and display modes of action similar to that of clonidine. Central alpha-adrenergic receptors are presumably involved. In the anaesthetized, normotensive rat St-404 is about 3,400 times less active than clonidine, whereas compound 44-549 is 5 times more effective in lowering arterial pressure. The hypotensive effect of TIQ is brought about by a mechanism of action which is different from that of clonidine. The alpha-sympatholytic properties of TIQ suggested previously by others are not confirmed by the experiments presented in this paper.

Animals↗
PubMed1979

In vitro relaxation of arteries and veins by prazosin: alpha-adrenergic blockade with no direct vasodilation.

Controversy exists regarding the mechanism by which prazosin lowers blood pressure without a marked increase in heart rate; a mechanism involving both sympatholytic activity and direct smooth muscle relaxation has been suggested. alpha-Adrenergic receptor blockade by prazosin is well documented and occurred to exogenous norepinephrine and to field stimulation in vitro in rat arteries and veins. A parallel shift of the norepinephrine concentration response curves in the aorta and mesenteric artery contrasted with a nonparallel shift and a marked depression of maximal norepinephrine responses in the inferior vena cava, portal, iliac and femoral veins. Nonspecific direct acting vasodilators will antagonize contractile responses to all agonists. However, prazosin (10(-8) M) specifically antagonized norepinephrine-induced responses. Concentration response curves to potassium chloride or to serotonin were not affected in these rat tissues. In addition, prazosin (up to 10(-6) M) did not significantly relax aortic tissue previously contracted with potassium chloride or serotonin, whereas the vasodilator, nitroglycerin, produced a clear relaxation. Prazosin only reduced the tone of vessels contracted with norepinephrine. These data indicate that prazosin exhibits minimal, if any, direct smooth muscle relaxant properties in concentrations higher than those producing alpha-adrenergic receptor blockade, and relaxes rat veins by a mechanism involving alpha-adrenergic receptor blockade.

Animals↗
PubMed1997

Renal protection in diabetes--an emerging role for calcium antagonists.

The combination of diabetes and hypertension increases the changes of progressive renal disorder and ultimately renal failure. Roughly 40% of all diabetics, whether insulin dependent or not, develop diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal disease in the western world and accounts for more than a quarter of all end-stage renal diseases. It is also a major cause of increased morbidity and mortality in diabetic patients. Increased arterial blood pressure is an early and common phenomenon in incipient and overt diabetic nephropathy. The relationship between arterial blood pressure and diabetic nephropathy is a complex one, diabetic nephropathy increasing blood pressure and blood pressure accelerating the course of nephropathy. Calcium antagonists antagonize preglomerular vasoconstriction. Furthermore, additional putative mechanisms include the ability to retard renal growth and possibly to attenuate mesangial entrapment of macromolecules and to attenuate the mitogenic effects of diverse growth factors. Calcium antagonists (except the old short-acting dihydropyridine drugs) reduce microalbuminuria and preserve kidney function in diabetic patients with incipient diabetic nephropathy. Long-term trials using the new long-acting dihydropyridine calcium antagonists for the treatment of patients with incipient nephropathy are still lacking. A recent 1-year randomized double-blind study in hypertensive insulin-dependent diabetic patients with diabetic nephropathy showed a more beneficial effect on the decline rate in the glomerular filtration rate of nisoldipine (long-acting dihydropyridine) than angiotensin-converting-enzyme (ACE) inhibition. The mean arterial blood pressure during the study based on 24-hour recordings was nearly identical, 103 (SD 9) and 101 (SD 11) mm Hg in the two groups. Furthermore, a recent 5-year randomized open study in hypertensive noninsulin-dependent patients with diabetic nephropathy has revealed the same beneficial effect of a calcium antagonist and ACE inhibition on the progression of nephropathy. In a third group treated with sympatholytic drugs, more than 50% of the subjects had a doubling of their creatinine as compared to less than 10% in the two other groups mentioned above. However, long-term studies are needed to consolidate these findings and expand them to insulin-dependent diabetic patients with diabetic kidney disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1976

Pharmacological inhibition of salivary glands: a possible therapy for sialosis and sialoadenitis. Effect of experimentally induced beta-receptor block on the rat parotid gland.

An increase of alpha-amylase concentration and specific amylase activity (correlated to protein content) was evident already after 3 days in the parotid glands of rats treated with 2 X 2 mg/day of propranolol hydrochloride. After separation of amylase into isoenzymes, only the specific isoamylase activities were enhanced. In contrast to treatment with a guanethidine derivative (guanoxane), these changes have persisted after 3 weeks. On the strength of these results, functional inhibition of the salivary glands (i.e. blockade of secretion by beta-sympatholytic agnets) is discussed as a therapeutical possibility for the management of sialosis and sialoadenitis.

Amylases↗
PubMed1977

Urethral closing pressure after spinal cord injury and its relationship to autonomic dysreflexia.

The evolution of patterns of neurogenic vesical dysfunction with emphasis on urethral resistance has been studied using a two-catheter urethral profile technique in 24 patients following acute spinal cord injury. Inappropriate urethral resistance to voiding appeared to result both from smooth and skeletal muscular activity and to some extent was dependent on the level of the spinal cord lesion. Autonomic dysreflexia was common, and responded to treatment with an alpha-sympatholytic agent.

Female↗
PubMed1978

Secondary prevention and associated drug therapy.

In secondary prevention, the treatment of serious disorders is undoubtedly necessary. This applies to the treatment of latent or manifest heart failure with digitalis glycosides, the treatment of coronary insufficiency with suitably active medicaments, and the administration of antiarrhythmics to patients with cardiac arrhythmias, who could be particularly endangered under certain circumstances. Raised arterial blood pressure, one of the most important risk factors of coronary heart disease, requires suitable drug treatment. Similarly, the additional administration of medicaments that affect lipid metabolism and of substances that lower raised uric acid levels together with a suitable diet is often inevitable. It is patently obvious that diabetes mellitus must be optimally controlled. Whether the long-term administration of beta-sympatholytics has a protective effect on the onset of sudden deaths through cardiac arrhythmias or on the incidence of reinfarction is, in the present state of knowledge, quite possible, but still not definitely proven. Different indications and dosages of the medicament, and thus the absence of standardized conditions, scarcely permit an assessment of the success of associated drug therapy in secondary prevention.

Coronary Disease↗
PubMed2004

Effects of epidural-and-general anesthesia combined versus general anesthesia alone on the venous hemodynamics of the lower limb. A randomized study.

Our hypothesis was that, due to its sympatholytic action, epidural anesthesia (EA) administered as part of anesthesia in abdominal surgery would generate a marked venous leg flow enhancement, thus aiding in the prevention of peroperative venous stasis. We studied, and comprehensively quantified the venous haemodynamic changes in the lower limb during and immediately after abdominal surgery performed under EA and general (GA) anesthesia combined, in comparison to GA alone. This is a prospective, randomized, controlled study, stratified for hypertension and smoking, comprising ASA 1-2 patients undergoing elective total abdominal hysterectomy. Those with peripheral vascular or chronic venous disease, prior DVT or BMI>35 were excluded. Eligible recruits received either GA (Group GA) (n = 10; age 36-65, median 50) alone or epidural anesthesia (EA) and GA combined (Group EA/GA) (n = 9; age 32-58, median 46). EA (L(1-2)) was administered using lignocaine 2%. Both groups had GA induced with fentanyl and propofol, maintained with N(2)O and isoflurane; larygoscopy was facilitated with vecuronium; analgesia was provided either with morphine (Group GA) or epidurally with 2% lignocaine boli (Group EA/GA). Hemodynamics were determined at the popliteal vein in the horizontal supine position at baseline (resting prior to anesthesia), post epidural (20 min after delivery of EA), post induction (15 min after laryngeal intubation), surgery (upon uterus removal) and recovery (30 min after extubation). There was no difference in the mean velocity[V(mean)] between the 2 groups at baseline (p = 0.35([Mann-Whitney])), and post induction (p = 0.5([Mann-Whitney])). However V(mean) was significantly higher in Group EA/GA than Group GA, both at surgery (point estimate[PE]: 1.8 cm/s; 95% CI: 0.01, 6.3 cm/s; p <0.05([Mann-Whitney])) and recovery (PE: 2.6 cm/s; 95% CI: 0.4, 5.1 cm/s; p = 0.02([Mann-Whitney])). Volume flow[V(Q)] was similar in the 2 groups at baseline and post induction (both, p >0.1([Mann-Whitney])), but was significantly higher in Group EA/GA at surgery (PE: 54 ml/min; 95% CI: 18, 159 ml/min; p = 0.045([Mann-Whitney])) and recovery (PE: 49 ml/min; 95% CI: 16, 129 ml/min; p=0.0037([Mann-Whitney])). Peak velocity, V(mean) and V(Q) increased significantly post epidural in Group EA/GA. Contrary to the venous leg flow attenuation in elective abdominal surgery under GA and upon its recovery, EA administered as part of GA is associated with a significant enhancement of both V(mean) and V(Q). This beneficial hemodynamic effect of EA at the vulnerable stage of recovery may be critically essential in light of enhanced blood viscosity, fibrinolytic shut-down, endothelial/platelet activation and immobility, acting in synergy with putative cardiorespiratory protection. The results of this study lend support to the preferential selection of combined EA/GA in subjects at high risk for venous thromboembolism, particularly when optimal DVT prophylaxis is practically unattainable due to limitations pertaining to the nature of surgery.

Adult↗
PubMed2003

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. METHODS AND RESULTS: Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). CONCLUSIONS: This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Adrenergic beta-Antagonists↗
PubMed1999

Digitalis.

Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.

Digitalis Glycosides↗
PubMed2003

Hypotension and reduced catecholamines in neuropeptide Y transgenic rats.

The neurons that control blood pressure express neuropeptide Y. Administered centrally, this neuropeptide reduces blood pressure and anxiety, together with lowering sympathetic outflow. The generation of neuropeptide Y transgenic rats overexpressing this peptide, under its natural promoter, has allowed us to examine the role of endogenous neuropeptide Y in the long-term control of blood pressure by the sympathetic nervous system. This study tested a hypothesis that endogenous neuropeptide Y acts to reduce blood pressure and catecholamine release. Blood pressure was measured by radiotelemetry in conscious male transgenic and nontransgenic littermates (control). Novel cage with cold water and forced swimming were used as stressors. Catecholamines were determined in 24-hour urine (baseline) and plasma (cold water stress) by a radioenzymatic assay. Blood pressures in baseline and during the stresses were significantly reduced in the transgenic rats. The lower blood pressure was associated with reduced catecholamines, lower decrease in pressure after autonomic ganglionic blockade, and increased longevity. Data obtained through the use of this transgenic rat model support and extend the evidence for the previously postulated sympatholytic and hypotensive effects of neuropeptide Y and provide novel evidence for an important physiological role of endogenous peptide in blood pressure regulation. As indicated by the increased longevity of these rats, in long-term regulation, these buffering actions of neuropeptide Y may have important cardiovascular protective effects against sympathetic hyperexcitation.

Animals↗
PubMed2004

Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings.

Although Mg2+ contributes to blood pressure regulation partly in terms of vasodilator action, its sympatholytic effect may also play an important role to control blood pressure. Thus, in the present study, we investigated the effect of Mg2+ on sympathetic tone and blood pressure. We studied its actions on the blood pressure response to hydralazine, a direct vasodilator, in conscious spontaneously hypertensive rats (SHRs), and to electrical stimulation in the pithed Sprague-Dawley rat; catecholamine release by peripheral sympathetic nerve endings; and the N-type Ca2+ channels of cultured neural cells. Intravenous Mg2+ infusion (MgSO4: 3x10(-6) mol/kg body weight/min) induced the greater hypotensive response to hydralazine with attenuated reflex tachycardia in SHRs. In pithed rats, Mg2+ infusion significantly attenuated the blood pressure elevation (2+/-2 mm Hg versus 27+/-6 mm Hg, P<0.01) in response to spinal electrical stimulation. In the perfused mesenteric arteries system, norepinephrine release was significantly attenuated (51+/-2%, P<0.01) by high Mg2+ concentration solution (4.8 mmol/L) compared with normal Mg2+ solution (1.2 mmol/L). When we applied the perforated whole-cell patch clamp method to nerve growth factor-treated PC12 cells, Mg2+ blocked voltage-gated Ca2+ currents in a concentration-dependent manner. The majority of the voltage-gated Ca2+ currents were carried through N-type channels, followed by L-type channels. Mg2+ blocked both of these channels. These findings suggest that Mg2+ blocks mainly N-type Ca2+ channels at nerve endings, and thus inhibits norepinephrine release, which decreases blood pressure independent of its direct vasodilating action.

Animals↗