The asymmetry of antimatter in the proton.

The fundamental building blocks of the proton-quarks and gluons-have been known for decades. However, we still have an incomplete theoretical and experimental understanding of how these particles and their dynamics give rise to the quantum bound state of the proton and its physical properties, such as its spin1. The two up quarks and the single down quark that comprise the proton in the simplest picture account only for a few per cent of the proton mass, the bulk of which is in the form of quark kinetic and potential energy and gluon energy from the strong force2. An essential feature of this force, as described by quantum chromodynamics, is its ability to create matter-antimatter quark pairs inside the proton that exist only for a very short time. Their fleeting existence makes the antimatter quarks within protons difficult to study, but their existence is discernible in reactions in which a matter-antimatter quark pair annihilates. In this picture of quark-antiquark creation by the strong force, the probability distributions as a function of momentum for the presence of up and down antimatter quarks should be nearly identical, given that their masses are very similar and small compared to the mass of the proton3. Here we provide evidence from muon pair production measurements that these distributions are considerably different, with more abundant down antimatter quarks than up antimatter quarks over a wide range of momenta. These results are expected to revive interest in several proposed mechanisms for the origin of this antimatter asymmetry in the proton that had been disfavoured by previous results4, and point to future measurements that can distinguish between these mechanisms.

Hemodynamic profile of neuropeptide Y in dogs: effect of ganglionic blockade.

The hemodynamic effects of neuropeptide Y (NPY) were examined over a dose range of 0.03-30 nmol/kg, i.v., in anesthetized open-chest, ventilated dogs with and without ganglionic blockade. In normal (non-ganglion-blocked) animals, NPY produced significant, dose-dependent, and sustained (lasting 15-45 min) increases in mean arterial blood pressure and systemic vascular resistance (SVR) with a threshold dose of 0.3 nmol/kg and a maximum effective dose of 10 nmol/kg. Cardiac index (CI) decreased at doses > 1 nmol/kg, but stroke volume was not altered; heart rate (HR) decreased significantly at and above the 3 nmol/kg dose. No significant changes were observed in the left ventricular dP/dt (LVdP/dt) or the contractility index (LVdP/dt divided by systolic pressure). In ganglion-blocked animals, pressor and SVR responses to NPY were similar to those seen in normal animals but HR was not affected and a small but significant decrease in CI was seen only at the 30 nmol/kg. Furthermore, whereas LVdP/dt of ganglion-blocked dogs increased significantly at and above the 1 nmol/kg dose, the contractility index increased slightly only with the 10 and 30 nmol/kg doses. These data indicate that NPY produces sustained hypertension in dogs secondary to peripheral vasoconstriction, has a weak, direct positive inotropic action on the heart, and lacks chronotropic effects.

Hemodynamic characterization of a novel neuropeptide Y receptor antagonist.

Defining the roles of the vasoconstrictor peptide neuropeptide Y (NPY) in the cardiovascular system is difficult due to lack of availability of specific NPY receptor antagonists. We report the in vivo NPY receptor blocking actions of a novel nonapeptide dimer, 1229U91 {(IleGluProDprTyrArgLeuArgTyrNH(2)(2)}, and describe its hemodynamic effects. In anesthetized normotensive rats, 1229U91 produced significant and dose-dependent reductions in NPY-reduced hemodynamic responses. 1229U91 (3-30 nmol/kg intravenously, i.v.) attenuated the pressor response (34 +/- 6-84 +/- 1%) and the increases in renal vascular resistance (RVR, 56 +/- 9-94 +/- 2%) produced by NPY (1 nmol/kg i.v.). Intravenous norepinephrine (NE)-induced hemodynamic responses were not altered by 1229U91. 1229U91 also produced dose-dependent inhibition of NPYinduced vasoconstrictor responses in anesthetized dogs and spontaneously hypertensive rats (SHR). These data demonstrate that 1229U91 is a selective NPY receptor antagonist. 1229U91 had no effect on resting hemodynamic variables in these preparations. In conscious SHR, 1229U91 did not produce significant changes in blood pressure (BP) or heart rate (HR) over a wide dose-range (15-1,500 nmol/kg i.v.). Lack of effect of the NPY receptor antagonist in SHR suggests that NPY does not contribute to the maintenance of BP in this hypertension model.

Cutaneous vasomotor effects of neuropeptide Y.

The effects of neuropeptide Y (NPY) were examined on the cutaneous microvascular blood flow (CMF) of the hindpaws in anesthetized rats. NPY (0.5-50 nmol/kg), infused intra-arterially into the hindpaw circulation, produced sustained dose-dependent increases in CMF (29 +/- 7% to 210 +/- 52%) indicating cutaneous vasodilation. Denervation of a hindpaw, ganglionic or alpha-adrenergic blockade significantly elevated the resting CMF indicating tonic vasoconstrictor sympathetic input to the cutaneous vasculature. In the denervated hindpaw or following ganglionic blockade, NPY produced sustained decreases in CMF (up to 51 +/- 8%) indicating vasoconstriction. Effects of the Y1 receptor agonist, (Leu31, Pro34) NPY were identical to those of NPY. The Y2 receptor agonist, NPY13-36 increased CMF of the intact hindpaw (24 +/- 10%-68 +/- 16% at 5-150 nmol/kg, i.a.) but did not affect CMF of the denervated hindpaw. NPY and (Leu31, Pro34)NPY, but not NPY13-36, produced significant pressor effects. These data suggest that: 1) NPY produces neurogenic cutaneous vasodilation via presynaptic Y2 receptor-mediated inhibition of sympathetic tone, 2) Y1 receptors may also exist presynaptically, however, it is likely that (Leu31, Pro34)NPY does not distinguish between Y1 and Y2 receptors, and 3) activation of postsynaptic Y1 receptors produces vasoconstriction which is unmasked only when the noradrenergic tone is eliminated.

Mechanisms of central endothelin-induced hypotension.

The aims of the present study were i) to determine the type of endothelin receptor(s) mediating the hypotension produced by central administration of endothelin-1 (ET-1), ii) to delineate the hemodynamic factors contributing to this hypotension and iii) to differentiate between the neural and cerebrovascular actions of ET-1. Towards these objectives, we monitoreal blood flow from the choroid plexus of the IVth cerebral ventricle (4CV) as an index of local cerebral blood flow (CBF); also, aortic blood flow (ABF) and cutaneous microvascular blood flow (CMF) of the hindpaw were monitored. In anesthetized, ventilated rats, ET-1 (1, 3 and 10 pmol) applied to the 4CV produced significant decreases in mean arterial blood pressure (15 +/- 4%, 34 +/- 3% and 37 +/- 3% respectively); hypotension was sustained at the two higher doses. ET-1 also produced a profound and sustained reduction in CBF (36 +/- 10%, 54 +/- 10% and 57 +/- 11% respectively). Prior administration of a low dose (1 nmol) of the ETA receptor selective antagonist, BQ-123 [cyclo (D-Trp-D-Asp-L-Pro-D-Val-L-Leu)], abolished only the central ET-1-induced hypotension; the decreases in CBF were not altered (57 +/- 11% and 56 +/- 6% respectively after 3 and 10 pmol). Pretreatment with a high dose (20 nmol) of BQ-123 attenuated but did not abolish the CBF response to 10 pmol of ET-1 (-26 +/- 1% vs. -57 +/- 11%).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotension to central endothelin-1: effect of glutamate receptor blockade.

Endothelin-1 (ET-1) produces hypotension via an action at glutamate-sensitive medullary cardiovascular sites. Here, we used excitatory amino acid (EAA) receptor antagonists to examine the possible role of an endogenous EAA in this neural action of central ET-1. ET-1 (3 pmol) applied to the IV ventricle of anesthetized, artificially ventilated rats elicited a sustained decrease in blood pressure (27 +/- 6%). Pretreatment with two EAA receptor antagonists, APV and CNQX (or MK-801 and CNQX), significantly attenuated the hypotension to central ET-1 (11 +/- 4%). Since these antagonists do not interact with endothelin receptors, we conclude that release of an endogenous EAA may contribute to the hypotensive action of central ET-1.

Hemodynamic responses evoked by endothelin from central cardiovascular neural substrates.

Endothelin-1 (ET-1, 3-10 pmol) applied to the fourth cerebral ventricle of anesthetized ventilated rats decreased mean arterial pressure (MAP, 37 +/- 5 to 55 +/- 5%), heart rate (13 +/- 7 to 21 +/- 3%), and renal blood flow (RBF, 41 +/- 7 to 45 +/- 8%; all values are means +/- SE) for 30-90 min. At a 30-pmol dose of ET-1, the decrease in MAP was preceded by an increase (58 +/- 16%). Micropneumophoresis of ET-1 (100-300 fmol) into discrete glutamate-responsive cardiovascular loci within the nucleus tractus solitarii (NTS), viz., the dorsal strip and the commissural subnucleus, produced depressor and bradycardic responses. However, central ET-1 was ineffective in evoking swallowing responses when microinjected into glutamate-responsive deglutitive sites in the NTS. These data suggest that, at low doses, ET-1 evokes hypotension and bradycardia by a specific neuronal action in the central nervous system; one site of action appears to be the cardiovascular neural substrates within the NTS; decreases in RBF may be secondary to the hypotension, since renal vascular resistance also decreased. In anesthetized nonventilated rats, ET-1 (3 and 10 pmol) applied to the fourth ventricle produced profound respiratory depression accompanied by a transient pressor effect. Thus centrally administered ET-1 can elicit complex cardiovascular responses by a direct action on cardiovascular substrates and/or indirectly via respiratory depression.

Functional evidence for the presence of a phosphoramidon-sensitive enzyme in rat brain that converts big endothelin-1 to endothelin-1.

Endothelin-1 (ET-1) is produced from its precursor, big endothelin-1 (BigET-1), by a putative endothelin-converting enzyme (ECE), but it is not known whether the enzyme is present in the brain. This study was conducted to examine the central hemodynamic effects of BigET-1 and to indirectly determine the presence of an ECE in rat brain. Cardiovascular effects of centrally administered BigET-1 and ET-1 were examined in anesthetized, ventilated rats. BigET-1 (100 pmol) or ET-1 (10 pmol) applied to the IV ventricle produced similar prolonged decreases in mean arterial pressure (MAP) and renal blood flow (RBF). Thus, peak decreases with BigET-1 were (mean +/- S.E.): MAP = -35 +/- 4%; RBF = -27 +/- 5%, while those with ET-1 were: MAP = -36 +/- 5%; RBF = -29 +/- 9%. Pretreatment with phosphoramidon, a metalloprotease inhibitor (90 nmol), abolished the hemodynamic responses elicited by BigET-1 (MAP = -9 +/- 2%; RBF = -3 +/- 2%) but not those produced by ET-1. These data indicate that; i) conversion of BigET-1 to ET-1 in the brain is essential for the expression of hemodynamic actions and ii) a metalloprotease capable of converting BigET-1 to ET-1 is present in rat brain.

Intrinsic sympathomimetic activity of labetalol.

In intact cats, cumulative doses (0.1-10 mg/kg i.v.) of labetalol produced dose-dependent decreases in heart rate and arterial blood pressure and dose-dependently reduced i.v. phenylephrine induced pressor responses. In spinal cats devoid of resting sympathetic tone, labetalol (1 mg/kg i.v.) produced a sustained elevation of heart rate and a transient fall in arterial blood pressure. In reserpine-pretreated, adrenalectomized cats, labetalol produced quantitatively the same effects as in spinal cats, indicating that the cardiovascular effects observed in cats with no resting sympathetic tone are due to a direct action of labetalol rather than via catecholamine release. The elevated heart rate due to labetalol in spinal cats was reduced by subsequent administration of the beta-adrenergic receptor antagonist, propranolol. Further, pretreatment with propranolol prevented the tachycardic and depressor effects of labetalol in spinal cats. In a separate group of spinal cats, labetalol administered in cumulative doses of up to 1 mg/kg i.v., produced graded increases in heart rate and also dose dependently reduced i.v. isoproterenol-induced tachycardic responses. Pindolol, a beta-adrenergic receptor antagonist with partial beta-agonist activity, produced similar effects in spinal cats at cumulative doses of 1-30 micrograms/kg. These results indicate that the alpha- and beta-adrenergic receptor antagonist, labetalol possesses partial beta-adrenergic receptor agonist activity. This intrinsic sympathomimetic action of labetalol appears to be more sustained on cardiac than on vascular beta-adrenergic receptors.

Cardiovascular effects of bromocriptine and lergotrile in renal and spontaneously hypertensive rats.

Cardiovascular effects of the dopamine receptor agonists, bromocriptine and lergotrile, were examined in renal hypertensive rats (RHR), spontaneously hypertensive rats (SHR) and in normotensive rats (NTR). In SHR, bromocriptine at 0.3 and 1.0 mg/kg i.p. and lergotrile at 0.3 mg/kg i.p. produced significant decreases in blood pressure and heart rate and the effects were prevented by haloperidol pretreatment. These results are consistent with the hypothesis that bromocriptine- and lergotrile-induced cardiovascular effects are due to a reduction in sympathetic tone via activation of neuronal dopamine receptors. In contrast to SHR, bromocriptine as well as lergotrile, at doses of 0.3 mg/kg i.p., were ineffective in RHR. Only at the 1 mg/kg i.p. dose, both the agents reduced blood pressure in RHR, but increased heart rate and only the effects of bromocriptine were antagonized by haloperidol. The magnitude and the duration of the hypotensive effect produced by both the agents were smaller in RHR than in SHR. The ganglion blocking agent, chlorisondamine, reduced blood pressure equally in RHR and SHR, but not in NTR, indicating a role for the sympathetic nervous system in the maintenance of high blood pressure in both SHR and RHR. It is further suggested that neuronal dopamine receptors that mediate reduction in resting sympathetic tone are less sensitive in RHR as compared to SHR.

Depression of reflex vagal bradycardia by a central action of phentolamine in the spinal cat.

Cats were anaesthetized with a mixture of alpha-chloralose and urethane and artificially ventilated. The spinal cord was transected at the C-1 level and the fourth cerebral ventricle cannulated. Phentolamine (500 microgram) administered into the fourth cerebral ventricle depressed the reflex vagal bradycardic responses elicited by intravenous pressor doses of noradrenaline. Enhancement of reflex bradycardia occurred following intracerebroventricular administration of L-DOPA (3.0 mg) which was reversed by subsequent administration of phentolamine into the fourth cerebral ventricle of spinal cats. These results suggest that central noradrenergic stimulation enhances and noradrenergic blockade suppresses the reflex vagal activation. In midcollicular decerebrate cats, intracerebroventricular administration of phentolamine reduced the reflex bradycardic responses elicited by intravenous noradrenaline. It is suggested that the action of phentolamine to depress baroreceptor mediated reflex vagal activation is on sites within the pontomedullary areas of the cat.

Species specificity of the platelet responses to 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine.

A semi-synthetic 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkylacetyl-GPC) was shown to be highly species selective in its capacity to cause platelet aggregation and serotonin release. No effects were elicited on the rat or mouse platelets while platelets from human, dog, cat, rabbit, guinea pig and horse were highly sensitive to alkylacetyl-GPC. The hypotensive activity in the rat was not associated with thrombocytopenia. Preliminary evidence suggested that the inability of platelets of the rat and mouse to respond to alkylacetyl-GPC was not due to a difference in plasma inactivation of the substance but due to a difference in platelet responsiveness per se. The data also support the concept that the potent hypotensive property of this substance readily observed in the rat, is a result of an effect which is platelet-independent.

Cardiovascular effects of chronic intraventricular administration of angiotensin II in dogs.

Intracerebroventricular administration of angiotensin II (AII), 1 microgram twice a day to mongrel dogs plus saline as the drinking fluid for 4 weeks produced a significant sustained elevation in systolic and diastolic blood pressures. The hypertensive state appeared to be due to an increase in total peripheral resistance. Fluid intake and urine output were elevated and there was a significant increase in body weight at the end of week 2, 3 and 4. Serum Na+ levels were significantly decreased and serum Ca++ levels significantly increased in the hypertensive animals. These studies indicate that increasing AII levels in the cerebrospinal fluid for a prolonged period of time produces a sustained hypertensive state only if the daily intake of sodium is increased and that the alterations in vascular resistance may be due to changes in the Na+ - Ca++ fluxes.

Inhibition of reflex vagal bradycardia by a central action of 5-hydroxytryptophan.

1 Vagally mediated reflex bradycardia was elicited in spinal cats with intravenous pressor doses of noradrenaline. Administration of 5-hydroxytryptophan (1.5 and 3 mg total dose) into the fourth cerebral ventricle reduced the reflex bradycardia. 2 Inhibition of central amino acid decarboxylase with R044602 prevented the effects of 5-hydroxytryptophan. After intravenous administration of 5-hydroxytryptophan, vagal reflex bradycardia was not affected. 3 Results suggest that 5-hydroxytryptophan acts in the CNS to inhibit baroreceptor-mediated vagal reflex bradycardia and that action is mediated via conversion to 5-hydroxytryptamine.

Enhancement of reflex vagal bradycardia following intracerebroventricular administration of methysergide in cats.

Metehysergide in total doses of 100, 200 and 400 micrograms injected into the fourth cerebral ventricle of cats potentiated the reflex bradycardic responses which were evoked by i.v. pressor doses of norepinephrine. Methysergide (400 micrograms) injected i.v., or intracerebroventricularly in vagotomized cats did not affect the reflex bradycardia. These results suggest that the enhancement of reflex vagal activation is due to an action of methysergide in the central nervous system. Intracerebroventricular methysergide significantly reduced the resting arterial pressure and heart rate, while i.v. administration caused only significant bradycardia. Carotid occlusion responses were depressed following both i.v. and intracerebroventricular methysergide. The magnitude of reductions in arterial pressure and heart rate following the injection of methysergide into the fourth cerebral ventricle were the same in vagotomized cats and in intact vagus preparations. It is suggested that depression of cardiovascular function is due to a central action of methysergide and is mediated by reduction in sympathetic outflow.

Central depression of carotid baroreceptor pressor response, arterial pressure and heart rate by 5-hydroxytryptophan: influence of supracollicular areas of the brain.

5-Hydroxytryptophan (5-htp) administered into the fourth cerebral ventricle of cats decreased resting arterial blood pressure, preganglionic sympathetic nerve activity and heart rate in both intact brain and midcollicular decerebrate preparations. The increases in sympathetic nerve discharge and blood pressure in response to bilateral carotid occlusion were reduced after 5-HTP administration when the brain was intact but not in midcollicular decerebrate preparations. Resting arterial pressure, heart rate and bilateral carotid occlusion response were not affected when the distribution of 5-HTP was confined to neural structures rostral to the midcollicular level by injection into the third or lateral cerebral ventricle with the cerebral aqueduct cannulated for drainage. Prior intracerebroventricular administration of an L-amino acid decarboxylase inhibitor (Ro 4-4602) prevented the effects of 5-HTP, indicating that depression is mediated via conversion to serotonin. These results suggest that serotenergic stimulation in the caudal brainstem or spinal cord produces depression of sympathetic outflow and decreases arterial blood pressure and heart rate. The bilateral carotid occlusion response is depressed by the brainstem serotonergic mechanisms which require the integrity of neural pathways connecting sub- and supracollicular areas of the brain. The possibility of reciprocal influence by the central serotonergic and adrenergic systems in cardiovascular control is discussed.

Depression and enhancement of baroreceptor pressor response in cats after intracerebroventricular injection of noradrenergic blocking agents: dependence on supracollicular areas of the brain.

The alpha-adrenergic blocking drugs, phentolamine and Hydergine, both act centrally at different sites to depress and enhance the pressor and sympathetic nerve response to decreased baroreceptor afferent input in anesthetized cats. Depression of the rise in blood pressure and sympathetic nerve discharge during bilateral carotid occlusion (BCO) followed injection of the agents into the 4th cerebral ventricle when the brain was intact but not when connections were interrupted at the midcollicular level by transection or lesion. Enhancement of responses occurred when drug distribution was confined to the brain rostral to the midcollicular level via injection into the 3rd cerebral ventricle with the cerebral aqueduct cannulated. Both agents decreased resting blood pressure and Hydergine decreased heart rate in intact and decerebrate preparations but not in 3rd ventricle-cerebral aqueduct experiments. We found that pretreatment with the noradrenergic precursor. L-dopa consistently prevented depression by phentolamine but was less effective against Hydergine. The results indicate that mechanisms which enhance and suppress the baroreceptor pressor response are normally operative in anesthetized cats and, furthermore, that neural pathways mediating the effects are ones connecting the caudal brainstem with supracollicular levels of the brain. It is further suggested that the pathways may be noradrenergic.