Consequences of the saphenous artery denervation under normal and chronically lowered blood pressure in rats

We studied constrictor responses of saphenous artery after sympathetic denervation in normotensive rats and rats with chronic regional hypotension. Abdominal aorta was partially occluded in Wistar rats distally to the renal arteries, lowering blood pressure in the hindquarters by about 40%, a week later to denervate saphenous artery the femoral nerve was cut. The density of periarterial nerve plexus and neurogenic responses of the vessel restored partially in 2 weeks and completely in 6 weeks after the surgery; the chronic hypotension did not modify the dynamics of reinnervation. Arteries of both groups of rats demonstrated higher sensitivity to noradrenaline during 6 weeks after denervation, whereas vessel sensitivity to serotonin was enhanced only in normotensive rats. Therefore, chronic hypotension may prevent postdenervation hypersensitivity of vascular smooth muscle to vasoconstrictors.     

Inhibition of vasoconstrictor responses by 6-keto-PGE1 in the feline mesenteric vascular bed

The effects of 6-keto-PGE₁ on vascular resistance and vascular responses to sympathetic nerve stimulation and vasoconstrictor hormones were investigated in the feline mesenteric vascular bed. Infusions of 6-keto-PGE₁ into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin II. The effects of 6-keto-PGE₁ and PGE₁ on vascular resistance and vasoconstrictor responses were quite similar and both substances inhibited responses to nerve stimulation and pressor hormones in a reversible manner. Responses to nerve stimulation, norepinephrine and angiotensin II were inhibited to a similar extent during infusion of 6-keto-PGE₁ and PGE₁. Results of these studies suggest that 6-keto-PGE₁, a newly identified prostaglandin metabolite, and PGE₁ possess the ability to inhibit the vasconstrictor effects of sympathetic nerve stimulation and pressor hormones by a nonspecific action on vascular smooth muscle in the feline small intestine.     

Raised tone reveals ATP as a sympathetic neurotransmitter in the porcine mesenteric arterial bed

The relative importance of ATP as a functional sympathetic neurotransmitter in blood vessels has been shown to be increased when the level of preexisting vascular tone or pressure is increased, in studies carried out in rat mesenteric arteries. The aim of the present study was to determine whether tone influences the involvement of ATP as a sympathetic cotransmitter with noradrenaline in another species. We used the porcine perfused mesenteric arterial bed and porcine mesenteric large, medium and small arteries mounted for isometric tension recording, because purinergic cotransmission can vary depending on the size of the blood vessel. In the perfused mesenteric bed at basal tone, sympathetic neurogenic vasocontractile responses were abolished by prazosin, an α₁-adrenoceptor antagonist, but there was no significant effect of α,β-methylene ATP, a P2X receptor-desensitizing agent. Submaximal precontraction of the mesenteric arterial bed with U46619, a thromboxane A₂ mimetic, augmented the sympathetic neurogenic vasocontractile responses; under these conditions, both α,β-methylene ATP and prazosin attenuated the neurogenic responses. In the mesenteric large, medium and small arteries, prazosin attenuated the sympathetic neurogenic contractile responses under conditions of both basal and U46619-raised tone. α,β-Methylene ATP was effective in all of these arteries only under conditions of U46619-induced tone, causing a similar inhibition in all arteries, but had no significant effect on sympathetic neurogenic contractions at basal tone. These data show that ATP is a cotransmitter with noradrenaline in porcine mesenteric arteries; the purinergic component was revealed under conditions of partial precontraction, which is more relevant to physiological conditions.     

Elevation of the vascular smooth muscle sensitivity to effects of constrictors after denervation and under decreased blood pressure

Changes in contractile activity of saphenous artery in normotensive rats and in rats with regional hypotension have been investigated. The abdominal aorta was partially occluded in Wistar rats distally to the renal arteries. Four weeks later, a 5-7-mm segment of the femoral nerve in one hindlimb was resected to denervate the saphenous artery. After two weeks, the isometric contraction of innervated and denervated saphenous artery segments was studied. In normotensive rats, the denervation augmented vessel sensitivity to noradrenaline, phenylephrine, serotonin, and KCl (in the presence of phentolamine). Chronic hypotension also augmented vessel sensitivity to constrictor agonists, whereas denervation did not result in further increase of sensitivity. In glyoxilic acid-stained preparations obtained from hypotensive rats, a reduced intensity of fluorescence of adrenergic fibers was observed. It was assumed that the higher sensitivity of vascular smooth muscle in hypotensive rats is due to functional disturbances of sympathetic innervation.     

The effects of periarterial nerve activation on coronary vessel tone in an isolated and perfused slab of beef ventricle.

The direct effects of extrinsic nerve stimulation on coronary artery tone are unclear because of the complications arising from alterations in myocardial dynamics which themselves alter flow. An isolated and perfused nonbeating slab of beef ventricle was utilized in the present experiments to eliminate secondary complications and the efects of periarterial nerve activation on coronary perfusion pressure were examined. It was found that stimulation induced vasoconstrictor responses which were enhanced by physostigmine, a cholinesterase inhibitor, and blocked by atropine. These responses were duplicated by exogenous acetylcholine both in the perfused preparation and in isolated strips of coronary artery. Although added noradrenaline gave vasodilatation, no response attributable to the release of noradrenaline from nerves was obtained. It is concluded that the coronary vasculature of the beef receives a cholinergic innervation and that its activation, especially under conditions of reduced transmitter degradation, may induce considerable coronary vessel constriction.     

Actions of prostacyclin (PGI2) on adrenergic neuroeffector transmission in the rabbit kidney.

In the Tyrode's perfused rabbit kidney PGI2 (1.3 x 10(-8)-3.3 x 10(-7)M) dose-dependently inhibited vasoconstrictor responses to sympathetic nerve stimulation, as did PGE2. The dose-effect curve of the two compounds differed, making PGI2 the less potent in the low concentration and the more potent in the high. PGI2 also inhibited the vasoconstrictor response to exogenous noradrenaline, but it had no effect on transmitter release. The main metabolite of PGI2, 6-keto-PGF1 alpha, was ineffective both on noradrenaline release and on vascular responses to nerve stimulation or exogenous noradrenaline. It is suggested that PGI2, if a significant renal prostaglandin, may modulate renal neuroeffector transmission post-junctionally, thereby forming a complement to the prejunctional action of PGE2.     

Changes in the microcirculatory bed and tissue metabolism in chronic regional arterial hypotension

Blood pressure was reduced in the hind part of rats by narrowing the aorta in regions distal to renal artery ostium. Resetting of microcirculatory bed (m. extensor hallicis propius) was revealed in arterial hypotension, characterized by resistance vessel dilatation ensuring the decrease in hydravlic resistance, thus facilitating blood supply and tissue metabolism normalization, irrespective of marked reduction in perfusion pressure.     

Inhibitory effects of pergolide on peripheral adrenergic neurotransmission in spontaneously hypertensive rats

Intraperitoneal injection of pergolide (12.5–500 μg/kg) produced dose-related and sustained arterial hypotension in anesthetized spontaneously hypertensive rats (SHR) which was accompanied by bradycardia at higher tested doses. During the time frame of hypotension produced by pergolide (50 μg/kg, i.p.), diastolic blood pressure and cardiac rate responses to electrical stimulation of the sympathetic outflow in pithed SHR were attenuated, whereas comparable responses induced by exogenous norepinephrine were unaffected. Pretreatment of SHR with sulpiride abolished pergolide-induced hypotension and prevented its inhibitory effect on neurogenic vasoconstrictor responses. Sulpiride alone had no effect on responses to electrical stimulation or injected norepinephrine. Yohimbine or vagotomy plus atropine did not attenuate the hypotensive effect of pergolide while hexamethonium or pithing reversed it; increments in pressure produced by pergolide after each of the latter interventions were probably mediated by postsynaptic alpha receptors, since vasoconstrictor responses to pergolide (10?100 μg/kg, i.v.) in pithed preparations were attenuated by phentolamine.The data suggest that pergolide lowers arterial blood pressure and cardiac rate by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of pergolide is at presynaptic (neuronal) dopamine receptors which are known to mediate inhibition of neurogenic release of norepinephrine.     

Patterns of constriction produced by vasoactive agents

The patterns of vasoconstriction produced by local infusions of constrictor agents and neurogenic stimuli are unique and varied. Although vasoconstrictors or neurogenic stimuli may produce similar increases in total resistance to blood flow, the effects on consecutive vascular segments may differ dramatically. Vasoconstrictors may affect primarily small vessels, large vessels, or a combination of both. The constrictor response may be restricted to precapillary vessels or may recruit both pre- and postcapillary vessels. The baroreceptors elicit a pattern of vasoconstriction distinct from that produced by electrical stimulation of a vasomotor nerve. Prearteriolar and venous resistance may contribute more than arterioles to increases in total vascular resistance produced by local infusions of vasoconstrictor agents or nerve stimulation. The constriction of large vessels also affects fluid filtration, vascular capacity, and the distribution of blood flow between shunt and exchange vessels. The waning of the resistance increase that occurs during prolonged infusions of vasoconstrictors varies, in part, as a function of the vessel segments that participate in the vasoconstrictor response. Large vessels participate in vasoconstrictor responses triggered by stimuli that impose a severe stress on the circulation. In contrast, small vessels participate primarily in normal vascular adjustments required to maintain blood pressure at the set point.     

Neurogenic constrictor response of isolated small renal arteries in rats after 2-week simulated microgravity

The study was aimed at investigation of the effects of 2-week tail suspension upon the constrictor responses of isolated small renal arteries in rats. 1st-2nd-order branches of renal artery were perfused with saline under the constant flow conditions. Constrictor responses to electrical stimulation of periarterial nerves, noradrenaline and serotonin were investigated. In post-suspension rats as compared to controls the response to nerve stimulation was slightly reduced during 15-Hz stimulation, but similar at smaller frequencies. Thus, simulated microgravity has no prominent effect of neurogenic responses of renal vessels, in agreement with non-changed density of periarterial adrenergic nerve plexus. Along with that, in post-suspension rats impairment of prejunctional sympathetic mechanisms might be compensated by augmented sensitivity of vascular smooth muscle to vasoconstrictors.     

Time-dependent changes in autonomic control of splanchnic vascular resistance and heart rate in ANG II-salt hypertension

Previous studies suggest that ANG II-induced hypertension in rats fed a high-salt (HS) diet (ANG II-salt hypertension) has a neurogenic component dependent on an enhanced sympathetic tone to the splanchnic veins and independent from changes in sympathetic nerve activity to the kidney or hind limb. The purpose of this study was to extend these findings and test whether altered autonomic control of splanchnic resistance arteries and the heart also contributes to the neurogenic component. Mean arterial pressure (MAP), heart rate (HR), superior mesenteric artery blood flow, and mesenteric vascular resistance (MVR) were measured during 4 control days, 14 days of ANG II delivered subcutaneously (150 ng·kg(-1)·min(-1)), and 4 days of recovery in conscious rats fed a HS (2% NaCl) or low-salt (LS; 0.1% NaCl) diet. Autonomic effects on MAP, HR, and MVR were assessed by acute ganglionic blockade with hexamethonium (20 mg/kg iv) on day 3 of control, days 1, 3, 5, 7, 10, and 13 of ANG II, and day 4 of recovery. MVR increased during ANG II infusion in HS and LS rats but remained elevated only in HS rats. Additionally, the MVR response to hexamethonium was enhanced on days 10 and 13 of ANG II selectively in HS rats. Compared with LS rats, HR in HS rats was higher during the 2nd wk of ANG II, and its response to hexamethonium was greater on days 7, 10, and 13 of ANG II. These results suggest that ANG II-salt hypertension is associated with delayed changes in autonomic control of splanchnic resistance arteries and the heart.     

Inhibition of peripheral adrenergic neurotransmission by lergotrile in spontaneously hypertensive rats

Intraperitoneal injection of lergotrile (0.5 mg/kg) produced arterial hypotension and bradycardia for 120 and 90 minutes, respectively, in anesthesized spontaneously hypertensive rats (SHR). During this time frame, lergotrile (0.5 mg/kg, i.p.) greatly attenuated diastolic blood pressure and cardiac rate responses to electrical stimulation (0.062-4 Hz) of the sympathetic outflow in pithed SHR, but had no significant effect on comparable increments in pressure and rate produced by exogenous norepinephrine (0.01–10 μg/kg, i.v.). Pretreatment of SHR with haloperidol (2 mg/kg, i.p.) prevented lergotrile-induced hypotension and partially reversed its inhibitory effect on neurogenic vasoconstrictor responses. Haloperidol alone had no significant effect on baseline arterial blood pressure or responses to sympathetic nerve stimulation. Administration of hexamethonium (20 mg/kg, i.v.) to SHR antagonized the hypotensive response to lergotrile (0.5 mg/kg, i.p.), although hydralazine (2 mg/kg, i.p.) still produced a marked reduction in pressure.These results suggest that lergotrile produces arterial hypotension and bradycardia primarily by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of lergotrile is at presynaptic (neuronal) dopamine receptors which are known to be inhibitory to neurogenic release of norepinephrine.     

Effect of captopril on neurally induced contraction and relaxation of mesenteric arteries of renal hypertensive rats

The effect of captopril treatment on neurally induced vasoconstrictor and vasodilator responses was examined in the isolated mesenteric arterial bed from normotensive and one-kidney, one clip hypertensive (1K1C) rats. In isolated mesenteric beds, electrical field stimulation (EFS) of perivascular nerves at basal tone induced a frequency-dependent increase in perfusion pressure that was greater in preparations from hypertensive rats compared with those from normotensive rats. Captopril treatment was associated with a decrease in vasoconstrictor responses in the hypertensive group compared with its non-treated control. Responses to norepinephrine (320 ng) were greater in hypertensive than normotensive groups; captopril reduced this response only in the hypertensive group. In preconstricted mesenteric arteries perfused with solutions containing guanethidine (5 microM) and atropine (1 microM), EFS elicited a frequency-dependent decrease in perfusion pressure that was abolished by tetrodotoxin (1 microM). Vasodilator responses to EFS were not affected by captopril treatment, although they were smaller in the hypertensive group. Acetylcholine (10 ng) induced similar decreases in perfusion pressure of normotensive and 1K1C groups; captopril did not influence these responses. These results indicate that captopril treatment does not affect the reduced neurogenic vasodilation but normalizes the augmented sympathetic-mediated vasoconstrictor responses of mesenteric resistance vessels of chronic 1K1C hypertensive rats.     

Mechanisms of vascular adaptation to long-term orthostatic gravitational loading

Frequent symptoms and serious complaints related to orthostatic intolerance are among the important reasons for investigating the long-term control mechanisms of blood vessels especially those of veins. Previously we studied perfused and superfused saphenous vein segments from rats maintained in head-up tilt position for two weeks. It was found that passive lumen capacity and acute pressure induced myogenic response of these vessels increased substantially without measurable change in wall thickness. Sympathetic component of the smooth muscle cell membrane potential determined in vivo was also significantly enhanced in this vein, but no such change was seen in the saphenous artery and in the brachial vessels. In a separate study, rarefaction of microvessels was found in the hind limb oxydative muscles after two-week tilting, while muscular water content was unaltered. These results suggest that long-term gravitational loading may induce adaptive rearrangement of the blood vessel functions. The aim of the present study was to quantitate and compare the density of nerve fiber terminals as well as their synaptic vesicle population in the wall of saphenous vein and artery from tilted rats to those obtained from rats which were maintained in horizontal, control position. It was hypothetized that adaptation of blood vessels to long-term gravitational loading might include also a morphological restructuring of the vascular adrenergic innervation.     

Endothelin-1 and U46619 potentiate selectively the venous responses to nerve stimulation within the perfused superior mesenteric vascular bed of the rat

The effects were examined of endothelin-1 and U46619 on the responses to perivascular nerve stimulation of the simultaneously perfused arterial and venous vessels of the superior mesenteric arterial bed of the rat. Stimulation of the nerves at 4-16 Hz for 30 s caused frequency dependent constrictions of both the arterial and venous vessels similar to those produced by bolus doses of exogenous noradrenaline (0.1-10 nmol). Infusion of either endothelin-1 (0.1 nM) or U46619 (1-3 nM) caused small (less than or equal to 5 mmHg) increases in arterial and venous perfusion pressures and selectively potentiated the venous, but not arterial, responses to nerve stimulation. Conversely, endothelin-1 and U46619 potentiated the responses of both the arterial and venous vessels to exogenous noradrenaline. Thus, as reported previously for the arterial vessels of the rat mesentery, the isolated venous vessels constrict to perivascular nerve stimulation in a frequency dependent manner. In addition, endothelin-1 and U46619 potentiate selectively the effects of nerve stimulation on the veins.     

Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) A2a receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of beta-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS A1 adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS A1 receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinejctions into the NTS of the selective A1 receptor agonist N6-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after beta-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS A1 receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral beta-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in iliac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS A1 receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS A1 receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and beta-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors.     

Actions of prostacyclin (PGI2) on adrenergic neuroeffector transmission in the rabbit kidney

In the Tyrode's perfused rabbit kidney PGI₂ (1.3 × 10⁻⁸-3.3 × 10^−7M) dose-dependently inhibited vasoconstrictor responses to sympathetic nerve stimulation, as did PGE₂. The dose-effect curve of the two compounds differed, making PGI₂ the less potent in the low concentration and the more potent in the high. PGI₂ also inhibited the vasoconstrictor response to exogenous noradrenaline, but it had no effect on transmitter release. The main metabolite of PGI₂, 6-keto-PGF_1α, was ineffective both on noradrenaline release and on vascular responses to nerve stimulation or exogenous noradrenaline. It is suggested that PGI₂,if a significant renal prostaglandin, may modulate renal neuroeffector transmission post-junctionally, thereby forming a complement to the prejunctional action of PGE₂.     

Endothelin-1 enhances responses to sympathetic nerve stimulation in endothelium-denuded and endothelium-intact rabbit ear arteries

In the rabbit isolated and endothelium-denuded ear artery, endothelin-1 (1–10 nM) elicited concentration-dependent vasoconstrictor responses. Lower concentrations of endothelin-1 (0.1, 0.3 and 1 nM) with little or no direct vasoconstrictor action significantly enhanced responses to sympathetic nerve stimulation in both endothelium-denuded and endothelium-intact arteries. The vasoconstrictor action of endothelin-1 and its enhancing effect on stimulation-induced responses were significantly decreased by the presence of the dihydropyridine-type calcium channel antagonist nicardipine (10 nM). The enhancing effect of low concentrations of endothelin-1 on responses to sympathetic nerve stimulation may play a role in the regulation of vascular tone.     

Atrial natriuretic factor attenuates sympathetic neuroeffector responses in hindlimb vasculature of rabbits

To determine whether atrial natriuretic factor (ANF) affects vasoconstrictor responses to electrical stimulation of sympathetic nerves or intra-arterial norepinephrine (NE), changes in perfusion pressure were measured during lumbar sympathetic nerve stimulation (LSNS, 1-8 Hz), or administration of NE (50-200 ng), in an isolated constant flow-perfused hindlimb of chloralose-anesthetized rabbit before and after intra-arterial infusion of ANF (0.5 ng.mL-1.min-1). ANF significantly attenuated responses to LSNS (relative potency, RP = 0.65) and to NE (RP = 0.47). We conclude that ANF attenuates vasoconstrictor responses to both LSNS and NE. Thus ANF alters sympathetic nervous system mediated changes in vascular resistance possibly at the neuroeffector site.     

The effect of cold on adrenergic neurotransmission in canine saphenous arteries and veins

The effect of severe cold (5 to 10 degrees C) on adrenergic neurotransmission was compared in the isolated cutaneous (saphenous) artery and vein of the dog. The vein contracted to sympathetic nerve stimulation at temperatures as low as 10 degrees C; higher temperatures were needed for the artery to contract. Both blood vessels contracted to exogenous norepinephrine at temperatures as low as 5 degrees C. However, the contractile response to exogenous norepinephrine was less in the saphenous artery, and contractions to high K+ solution were depressed by cooling more in the artery than in the vein. During electrical stimulation of the sympathetic nerves in saphenous arteries and veins previously incubated with labeled norepinephrine, progressive cooling from 37 to 5 degrees C caused a sharp decline in overflow of [3H]norepinephrine and its metabolites. However, overflow of labeled norepinephrine in both blood vessels continued at very cold temperatures. Thus the inability of the saphenous artery to contract to sympathetic nerve stimulation at 10 degrees C can be explained by a greater sensitivity of the arterial smooth muscle to the direct depressant effect of cold, rather than to a differential release or metabolism or norepinephrine in the arterial wall or a loss of responsiveness to norepinephrine at very cold temperatures.