Enhanced vascular responses to noradrenaline in isolated omental arteries from patients with advanced cirrhosis: evidence against intrinsic vascular hyporeactivity in cirrhosis.
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Humans↗
Biomedical subjects
J A Angus
Publications and source records attributed to J A Angus.
Evidence against an action of mibefradil at N-type voltage-operated calcium channels.
Mibefradil is a tetralol derivative that inhibits cloned and native T-type voltage-operated calcium channels (VOCCs) at an IC50 of 1 microM and with an apparent 15-fold selectivity for T- over L-type VOCCs. Recent electrophysiological studies in Xenopus oocytes and inhibition of noradrenaline release studies in human isolated right atria concluded that mibefradil (0.3-3 microM) can block N-type VOCCs like omega-conotoxin GVIA. We tested this hypothesis in rat and guinea pig isolated driven left atria and rat vas deferens in response to sympathetic nerve stimulation. Mibefradil (3 microM) did not inhibit the inotropic responses to sympathetic electrical field stimulation in atria. In contrast, these responses were blocked by GVIA (10 nM) and tetrodotoxin (TTX 0.1 microM). In rat vas deferens, pretreated with benextramine (BNX 10 microM), contractions considered to be due to transmitter ATP evoked by electrical field stimulation were blocked by: (a) TTX 0.1 microM, (b) P2x receptor desensitisation (alphabeta-MeATP 100 microM), and (c) GVIA (pIC50 9.04+/-0.15, n=5). In contrast, mibefradil (0.3-30 microM) had no effect on these N-type VOCC-sensitive sympathetic nerve responses. Potassium (62 mM K+) and alphabeta-MeATP-induced contractions were unaffected by GVIA (10 nM), but mibefradil inhibited the potassium-induced contractions with a pIC50 6.02+/-0.08 (n=5), consistent with a T- and L-type VOCC blocking action on the postjunctional smooth muscle. We conclude that mibefradil up to 30 microM does not block N-type VOCCs in these isolated intact tissue assays of sympathetic nerve-muscle transmission. Therefore, at least in these tissues, mibefradil can be used to define T- and L-type VOCC activities at submicromolar and micromolar concentrations in sympathetic nerve-mediated responses.
Animals↗
Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens.
1. The interaction between the cannabinoid agonists, WIN 55,212-2 or CP 55,940 with the CB(1) receptor-selective antagonists, SR141716A or LY320135 was investigated using the rat electrically-stimulated vas deferens bioassay. 2. Tissues were stimulated by single-field pulses (150 V, 0.5 ms) delivered every 30 mins. In the presence of nifedipine (3 microM), agonists elicited a concentration-dependent inhibition of the contractile response, with pEC(50) values of 7.93 and 6.84 for WIN 55,212-2 and CP 55,940, respectively. 3. SR141716A and LY320135 caused parallel dextral displacements of the agonist concentration-response curves. However, the shift of the agonist curves by either antagonist was accompanied by a concentration-dependent enhancement of basal (agonist-independent) tissue contraction. 4. Addition of the amidase inhibitor, phenylmethylsulphonylfluoride (200 microM), resulted in a significant reduction of the basal twitch response, an effect consistent with the presence of tonic receptor activation mediated by the endogenous cannabinoid, anandamide. 5. In light of these findings, we propose a theoretical model of competitive agonist-antagonist interaction in the presence of endogenous agonist tone that was used to derive an optimized analytical approach for the determination of antagonist potency estimates under conditions of tonic receptor activation. 6. This approach yielded pK(B) estimates for SR141716A and LY320135 that were in good agreement with their activity at cannabinoid CB(1) receptors. 7. It is concluded that the rat vas deferens contains prejunctional cannabinoid CB(1) receptors that are under tonic activation from endogenous substances; under these conditions our analytical approach is preferable to the standard methods for the determination of antagonist potency.
Animals↗
Targetting voltage-gated calcium channels in cardiovascular therapy.
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Animals↗
Pharmacological characterisation of cannabinoid CB(1) receptors in the rat and mouse.
The role of cannabinoid CB(1) receptors in sympathetic neurotransmission was characterised in nerve-mediated responses of isolated right atria, vasa deferentia and small mesenteric resistance arteries using the cannabinoid CB(1) receptor agonists Delta(9)-tetrahydrocannabinol, CP 55,940 and anandamide and the cannabinoid CB(1)-selective antagonist SR 141716A. In the mouse vas deferens, the twitch response was completely inhibited by each of the putative cannabinoid receptor agonists with pIC(50) values of CP 55,940, 9.2+/-0.1; Delta(9)-tetrahydrocannabinol, 8.4+/-0.1; anandamide, 7.1+/-0.1. SR 141716A 10-100 nM was a competitive antagonist of all three agonists with a pK(B) value of 8.4-8.6, consistent with an interaction at the cannabinoid CB(1) receptor. In the rat vas deferens CP 55,940 (0.01-10 microM) inhibited the contractions to a significant extent (88.5+/-0.5% at 10 microM; pIC(50) of 7.1+/-0.1) while Delta(9)-tetrahydrocannabinol and anandamide (both up to 10 microM) were inactive. CP 55,940 exhibited low potency in rat compared with mouse vas deferens and the rat concentration-response curve was not competitively antagonised by SR 141716A (100 nM) or SR 144528 (10 nM-10 microM), suggesting an interaction at a receptor(s) distinct from cannabinoid CB(1) or CB(2). Sympathetic nerve-induced tachycardia in rat and mouse atria, and rat mesenteric artery smooth muscle contractile responses to perivascular nerve stimulation, were not inhibited by Delta(9)-tetrahydrocannabinol, CP 55,940 or anandamide up to 1 microM. These data indicate that cannabinoid CB(1) receptor activation inhibits sympathetic neurotransmission only in the mouse vas deferens and thus point to species and regional differences in cannabinoid CB(1) receptor involvement in pre-synaptic inhibition of sympathetic neurotransmission and CP 55,940 may have inhibitory actions in rat vas deferens unrelated to cannabinoid receptor activity.
Animals↗
Cardiovascular and autonomic effects of omega-conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays.
1. The effects of a novel N-type voltage-operated calcium channel antagonist, omega-conotoxin CVID, were compared with omega-conotoxin MVIIA on sympathetic-evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their effects were also compared on blood pressure and cardiovascular reflexes in conscious rabbits. 2. The pIC(50) values for MVIIA and CVID, respectively, for inhibiting sympathetic-evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA - plog MA), for MVIIA and CVID were 2 and 10. The offset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization. 3. In the conscious rabbit, CVID and MVIIA (100 microg kg(-1) i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal- and sympathetic-mediated components of the baroreflex, but had no effect on the vagal nasopharyngeal reflex. The orthostatic reflex to 90 degrees tilt was blocked by MVIIA with sustained postural hypotension for > or = 90 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly. 4. Neither CVID nor MVIIA (3 microg kg(-1) i.t.) significantly altered cardiovascular variables or autonomic reflexes. 5. In conclusion, CVID appears to be relatively weak at inhibiting the reflex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N-type calcium channel selectivity.
Animals↗
Quantitative analysis of vascular to cardiac selectivity of L- and T-type voltage-operated calcium channel antagonists in human tissues.
1. Classical L-type voltage-operated calcium channel (VOCC) antagonists dilate blood vessels, depress myocardial contractility and slow cardiac conduction. 2. We compared four L-type VOCC antagonists and a novel tetralol derivative, mibefradil, reportedly 10-fold more selective for T- (transient) over L-type VOCC in two in vitro assays of human tissue, namely isolated small arteries from the aortic vasa vasorum in a myograph and right atrial trabeculae muscle under isometric force conditions. 3. In arteries contracted with K+ (62 mmol/L), the relaxation pIC50 values for the VOCC antagonists felodipine, nifedipine, amlodipine, verapamil and mibefradil were 8.30, 7.78, 6.64, 6.26 and 6.22, respectively. In atrial trabeculae, the pIC50 values to inhibit the inotropic response to a submaximal concentration of isoprenaline (6 nmol/L) for felodipine, nifedipine, verapamil, amlodipine and mibefradil were 7.21, 6.95, 6.91, 5.94 and 4.61, respectively. 4. Taking the anti-log (pIC50 vessel-pIC50 atrium) the vascular relaxation to cardiac depression potency ratios for mibefradil, felodipine, nifedipine, amlodipine and verapamil were 41, 12, 7, 5 and 0.22, respectively. 5. We conclude that, in human tissue assays, perhaps T- over L-type VOCC selectivity confers the most favourable vascular selectivity on mibefradil. Alternatively, splice variants of L-type VOCC in the vasculature (CaV1.2b) may be more sensitive to mibefradil than the splice variants in the heart (CaV1.2a).
Aorta↗
Postural hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension.
OBJECTIVE: To determine the relative importance of the cardiac and vascular sympathetic components of the orthostatic response to 90 degrees head-up tilt after N-type calcium-channel blockade in normotensive (sham renal cellophane wrap) and hypertensive (renal wrap) conscious rabbits. METHODS: The effects of N-type calcium-channel blockade with omega-conotoxin GVIA (omega-CTX, 10 microg/kg i.v. bolus) were assessed in the absence or presence of cardiac block by propranolol and methscopolamine. These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus). RESULTS: In vehicle (0.9% saline) treatment groups, the response to tilt consisted of a small pressor effect (4 +/- 2 and 7 +/- 1 mmHg) and tachycardia (29 +/- 6 and 17 +/- 6 beats/min) in sham (n = 6) and wrap (n = 5) rabbits, respectively. After prazosin administration (with cardiac block), there were significant falls in MAP of 3 +/- 1 and 7 +/- 2 mmHg in sham (n = 7) and wrap (n = 6) rabbits, respectively, in response to tilt omega-CTX caused postural hypotensive responses of 8 +/- 2 and 13 +/- 2 mmHg in sham (n = 6) and wrap (n = 7) rabbits, respectively, and 7 +/- 1 and 14 +/- 2 mmHg in sham (n = 7) and wrap (n = 7) rabbits with prior cardiac block. Similarly, mecamylamine caused falls in MAP of 8 +/- 1 and 10 +/- 2 mmHg in response to tilt in sham (n = 6) and wrap (n = 9) animals, respectively. CONCLUSION: Sympathetic vasoconstrictor effectors are primarily responsible for maintaining blood pressure during tilt in conscious rabbits. The postural hypotension caused by sympatholytic agents is about double in hypertensive rabbits, and N-type calcium-channel blockade is as effective as ganglion blockade at inducing this syndrome.
Adrenergic alpha-Agonists↗
Structure and the resistance amplifier in hypertension: reply to the dissenters.
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Animals↗
Role of NPY Y1 receptors in cardiovascular control in the conscious rabbit.
Prejunctional neuropeptide Y (NPY) Y1 receptors on cardiac sympathetic neurons mediate transient inhibition of chronotropic responses in rabbit isolated right atria. The function of these receptors remains speculative. We investigated a possible functional role for these receptors in modulation of the baroreceptor-heart rate (HR) reflex in the conscious rabbit. Mean arterial pressure (MAP) responses to a range of doses of the Y1 receptor agonist [Leu31,Pro34]NPY (1-8 microg/kg, i.v.) were constructed in ganglion-blocked rabbits. After administration of the selective Y1 receptor antagonist GR231118(150 microg/kg, i.v.), two-point [Leu31,Pro34]NPY dose-pressor responses were assessed. Linear regression analysis of the relation between the shift in the [Leu31,Pro34]NPY dose-pressor response lines against time was used as an estimate of the functional half-life of GR231118. GR231118 shifted the two-point [Leu31,Pro34]NPY dose-pressor response relation by 10- to 30-fold. A single estimate of the functional half-life of a bolus dose of GR231118 was 25 +/- 2 min. This determination allowed a steady-state Y1-receptor blockade to be established by a bolus and infusion. In a separate group of rabbits, the baroreceptor-HR reflex was assessed before and 30 min after administration of GR231118 (150 microg/kg bolus, then 150 microg/ kg/h, i.v.). GR231118 caused an initial transient pressor response and bradycardia, followed by a depressor response and a more sustained tachycardia. Infusion of GR231118 had no effect on the baroreceptor-HR reflex. Prejunctional Y1 receptors appear not to mediate a tonic inhibition of cardiac sympathetic neurotransmission in the conscious rabbit during physiological manipulations in MAP. However, activation of postjunctional Y1 receptors by neuronal or circulating NPY may be important in maintenance of vascular tone in the conscious rabbit.
Animals↗
Role of disulfide bridges in the folding, structure and biological activity of omega-conotoxin GVIA.
Omega-Conotoxin GVIA (GVIA), an N-type calcium channel blocker from the cone shell Conus geographus, is a 27 residue polypeptide cross-linked by three disulfide bonds. Here, we report the synthesis, structural analysis by (1)H NMR and bioassay of analogues of GVIA with disulfide bridge deletions and N- and C-terminal truncations. Two analogues that retain the crucial Lys-2 and Tyr-13 residues in loops constrained by two native disulfide bridges were synthesised using orthogonal protection of cysteine residues. In the first analogue, the Cys-15-Cys-26 disulfide bridge was deleted (by replacing the appropriate Cys residues with Ser), while in the second, this disulfide bridge and the eight C-terminal residues were deleted. No activity was detected for either analogue in a rat vas deferens assay, which measures N-type calcium channel activity in sympathetic nerve, and NMR studies showed that this was due to a gross loss of secondary and tertiary structure. Five inactive analogues that were synthesised without orthogonal protection of Cys residues as part of a previous study (Flinn et al. (1995) J. Pept. Sci. 1, 379-384) were also investigated. Three had single disulfide deletions (via Ser substitutions) and two had N- or C-terminal deletions in addition to the disulfide deletion. Peptide mapping and NMR analyses demonstrated that at least four of these analogues had non-native disulfide pairings, which presumably accounts for their lack of activity. The NMR studies also showed that all five analogues had substantially altered tertiary structures, although the backbone chemical shifts and nuclear Overhauser enhancements (NOEs) implied that native-like turn structures persisted in some of these analogues despite the non-native disulfide pairings. This work demonstrates the importance of the disulfides in omega-conotoxin folding and shows that the Cys-15-Cys-26 disulfide is essential for activity in GVIA. The NMR analyses also emphasise that backbone chemical shifts and short- and medium-range NOEs are dictated largely by local secondary structure elements and are not necessarily reliable monitors of the tertiary fold.
Amino Acid Sequence↗
Pharmacology of coronary artery bypass grafts.
Spasm of arterial and venous graft conduits can occur both during harvesting and after the graft is connected. Attempts to overcome spasm during harvesting by probing or hydraulic distension can cause structural damage to the graft, which may impair short- and long-term patency. After a coronary artery bypass graft is connected, spasm can cause major problems with myocardial perfusion. To select the best pharmacologic agent to prevent or reverse vasoconstriction in a graft requires an understanding of the reactivity of that particular type of graft to vasoconstrictor and vasodilator agents. The pharmacologic reactivity of venous and arterial graft conduits has been documented through extensive studies of isolated vessels in the organ bath and of in situ grafts in the body. In this review we summarize the current state of knowledge of the reactivity of arterial and venous grafts to vasoconstrictor and vasodilator agents and describe the practical application of this knowledge in the operating room and in the postoperative period.
Arteries↗
Heterogeneity of prejunctional NPY receptor-mediated inhibition of cardiac neurotransmission.
Neuropeptide Y (NPY) has been proposed as the candidate inhibitory peptide mediating interactions between sympathetic and vagal neurotransmission in several species, including man. Here, we have defined the NPY receptors involved in modulation of cardiac autonomic neurotransmission using receptor-selective agonists and antagonists in the rabbit and guinea-pig isolated right atria. In isolated atrial preparations, sympathetically-mediated tachycardia (ST; with atropine 1 microM) or vagally-mediated bradycardia (VB; with propranolol 0.1-1 microM) in response to electrical field stimulation (EFS, 1-4 pulses) were tested 0-30 min after incubation with single concentrations of vehicle, NPY (0.01-10 microM), the Y2 receptor agonist N-Acetyl-[Leu28,31]NPY(24-36) (termed N-A[L]NPY(24-36)) or the Y1 receptor agonist [Leu31,Pro34]NPY (LP). The effect of NPY on the concentration-chronotropic response curves to isoprenaline and bethanechol were also assessed. Guinea-pig atria: NPY and N-A[L]NPY(24-36) caused concentration-dependent inhibition of VB and ST to EFS. Both peptides caused maximal inhibition of VB and ST within 10 min incubation and this remained constant. LP caused a concentration-dependent, transient inhibition of ST which was antagonized by the Y1-receptor antagonist GR231118 (0.3 microM), with apparent competitive kinetics. Rabbit atria: NPY (1 or 10 microM) had no effect on VB at any time point, but both NPY and LP caused a transient (approximately 10 min) inhibition of sympathetic tachycardia. This inhibition could be prevented by 0.3 microM GR231118. N-A[L]NPY(24-36) had no effect on ST. NPY had no effect on the response to beta-adrenoceptor stimulation by isoprenaline nor muscarinic-receptor stimulation by bethanechol in either species. Thus, in the guinea-pig, NPY causes a stable inhibition of both VB and ST to EFS via Y2 receptors and transient inhibition of ST via Y1 receptors. In contrast in the rabbit, NPY has no effect on the cardiac vagus and prejunctional inhibition of ST is transient and mediated by a Y1-like receptor (rather than Y2). Therefore it would be surprising if NPY plays a functional role in modulation of cardiac neurotransmission in the rabbit.
Animals↗
Neuropeptide Y is a prejunctional inhibitor of vagal but not sympathetic inotropic responses in guinea-pig isolated left atria.
1. The effects of NPY and related peptides were examined on basal contractile force and nerve-mediated inotropic responses to electrical field stimulation of the guinea-pig isolated left atrium. 2. Electrical field stimulus (EFS)-inotropic response curves were constructed by applying 1-64 trains of four field pulses (200 Hz, 0.1 ms duration, 100 V) across isolated left atria (paced at 4 Hz, 2 ms, 1-4 V) within the atrial refractory period. Curves were constructed in presence of vehicle, propranolol (1 microM) or atropine (1 microM) to determine appropriate stimulus conditions. 3. The effects of PYY (1-10,000 nM), NPY (0.01-10 microM), N-Ac-[Leu28,31]NPY(24-36) (N-A[L]NPY(24-36); 0.01-10 microM) and clonidine (0.1-1000 nM) were examined on the positive and negative inotropic responses to EFS (eight trains, four pulses per refractory period). 4. NPY-related peptides had no effect on basal force of contraction nor on the inotropic concentration-response curves to bethanechol or isoprenaline. All three peptides inhibited vagally-mediated negative inotropic responses; rank order of potency PYY>NPY> or =N-A[L]NPY(24-36) was consistent with an action at prejunctional Y2-receptors. Clonidine concentration-dependently inhibited sympathetic inotropic responses. However, PYY, NPY and N-A[L]NPY(24-36) failed to mediate any significant inhibition of the positive inotropic response to EFS. 5. These data demonstrate that NPY is an effective inhibitor of vagal but not sympathetically-mediated inotropic responses in the guinea-pig isolated left atria. This may suggest that endogenously co-released NPY is important in mediating cross talk between efferent components of the autonomic nervous system modulating cardiac contractility, acting overall to sustain positive inotropic responses.
Adrenergic alpha-Agonists↗
Role of N-type calcium channels in autonomic neurotransmission in guinea-pig isolated left atria.
1. Calcium entry via neuronal calcium channels is essential for the process of neurotransmission. We investigated the calcium channel subtypes involved in the operation of cardiac autonomic neurotransmission by examining the effects of selective calcium channel blockers on the inotropic responses to electrical field stimulation (EFS) of driven (4 Hz) guinea-pig isolated left atria. In this tissue, a previous report (Hong & Chang, 1995) found no evidence for N-type channels involved in the vagal negative inotropic response and only weak involvement in sympathetic responses. 2. The effects of cumulative concentrations of the selective N-type calcium channel blocker, omega-conotoxin GVIA (GVIA; 0.1-10 nM) and the non-selective N-, P/Q-type calcium channel blocker, omega-conotoxin MVIIC (MVIIC; 0.01-10 nM) were examined on the positive (with atropine, 1 microM present) and negative (with propranolol, 1 microM and clonidine, 1 microM present) inotropic responses to EFS (eight trains, each train four pulses per punctate stimulus). 3. GVIA caused complete inhibition of both cardiac vagal and sympathetic inotropic responses to EFS. GVIA was equipotent at inhibiting positive (pIC50 9.29+/-0.08) and negative (pIC50 9.13+/-0.17) inotropic responses. MVIIC also mediated complete inhibition of inotropic responses to EFS and was 160 and 85 fold less potent than GVIA at inhibiting positive (pIC50 7.08+/-0.10) and negative (pIC50 7.20+/-0.14) inotropic responses, respectively. MVIIC was also equipotent at inhibiting both sympathetic and vagal responses. 4. Our data demonstrates that N-type calcium channels account for all the calcium current required for cardiac autonomic neurotransmission in the guinea-pig isolated left atrium.
Animals↗
Roles of key functional groups in omega-conotoxin GVIA synthesis, structure and functional assay of selected peptide analogues.
The contributions of various functional groups to the pharmacophore of the N-type calcium-channel blocker, omega-conotoxin GVIA (GVIA), have been investigated using structural and in-vitro functional studies of analogues substituted at one or two positions with non-native residues. In most cases the structure of the analogue was shown to be native-like by 1H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) were employed to monitor N-type calcium-channel activity. The data provide a more detailed picture of the roles in GVIA structure and activity of the crucial Lys2 and Tyr13, as well as all other positively charged residues, Tyr22, the hydroxyproline residues and the C-terminal amido moiety, many of which were identified as being important for activity in an alanine scan [Lew et al. (1997) J. Biol. Chem. 272, 12014-12023]. Substitutions of Lys2 with nonstandard amino acids and arginine quantified the roles of the length and charge of the Lys side chain. The orientation of the Tyr13 side chain and its hydroxyl moiety was shown to be important by substitution with d-Tyr and the d-form and l-form of the constrained analogue 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Tic(OH)]. The roles of the Hyp10 and Hyp21 hydroxyl groups, investigated by proline substitutions, appear to be more structural (as monitored by NMR) than functional, although small decreases in potency were observed in some assays. The reversibility of the channel blockade was also studied, and several analogues with faster wash-out characteristics than native GVIA were identified. Rapid reversibility (as in the case of omega-conotoxin MVIIA) may be beneficial for therapeutic applications. Disubstituted analogues revealed some interesting cooperative effects, which were not predicted from single-residue substitutions. A disubstituted chimera of GVIA and omega-conotoxin MVIIA was more potent than either native molecule. The more detailed description of the GVIA pharmacophore obtained here provides a better basis for the future design of truncated peptide and peptidomimetic analogues.
Amino Acid Sequence↗
Enhanced total peripheral vascular responsiveness in hypertension accords with the amplifier hypothesis.
BACKGROUND: Increases in vascular resistance (or the reciprocal, vascular conductance) in response to constrictor drugs are amplified (or attenuated) in the hindquarter vascular bed of hypertensive rats and rabbits. However, such changes have not been observed for the total peripheral circulation. OBJECTIVE: To assess whether the vascular amplifier applies to the total peripheral circulation in conscious hypertensive rabbits. METHODS: Rabbits were implanted with a flow probe for measuring cardiac output, a left atrial catheter for infusing dilator (adenosine) and constrictor (methoxamine) drugs, and ear artery and vein catheters for measuring mean arterial pressure (MAP) and for giving ganglion blockade. Data from full dose-total peripheral resistance (TPR) or total peripheral conductance (TPC) response curves to adenosine and methoxamine were combined into a logistic function extending from near full dilatation to near maximum constriction. RESULTS: Changes in MAP induced by methoxamine and adenosine were markedly greater in the 'wrap' rabbits (those with renal cellophane wrapping) compared with the sham animals. In the 'wrap' rabbits, the slopes and ranges of the adenosine-TPR response curve and the methoxamine-TPC response curve were 200% and 60%, respectively, of sham values. These data show that TPR changes are amplified, and TPC changes attenuated, to dilator and constrictor stimuli. The relationship between dose-average vascular radius (r; based on Poiseuille's law) over the full range of vascular tone showed that r was narrower in hypertension, but, in contrast to TPR, the degree of narrowing was almost the same between maximum dilatation and constriction. CONCLUSION: The total peripheral circulation in experimental hypertension is a TPR amplifier, or TPC attenuator, in the rabbit, consistent with well-established data in the major vascular beds.
Adenosine↗
Exogenous NPY modulation of cardiac autonomic reflexes and its pressor effect in the conscious rabbit.
1. Neuropeptide Y (NPY) may inhibit sympathetic and vagal transmission via presynaptic Y2 receptors and cause vasoconstriction via postsynaptic Y1 receptors. We examined the effects of NPY and related peptides on cardiovascular parameters and autonomic reflexes in the conscious rabbit. Further, the postjunctional effects of NPY and related peptides were assessed on acetylcholine (ACh) and isoprenaline agonist dose-chronotropic response curves. 2. In conscious rabbits the cardiac baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch like and nasopharyngeal reflexes were assessed in control, propranolol-treated or methscopolamine-treated (baroreflex only) groups, before and 30 min after i.v. administration of NPY (10 microg kg[-1] + 5 microg kg[-1] min[-1]) or vehicle (saline, 10 ml h[-1]). The effects of equivalent pressor doses of [Leu31, Pro34]NPY or methoxamine on the baroreflex were also examined. In separate animals, dose-heart rate (HR) response curves to isoprenaline or ACh were constructed before and 15 min after administration of NPY, [Leu31,Pro34]NPY (ACh only) or [Leu31,Pro34]NpY + sodium nitroprusside (ACh only). 3. Administration of NPY-receptor agonists caused sustained bradycardia (in the absence of methscopolamine) and rightward shifts of the barocurves in all 3 groups. The range of sympathetically-mediated tachycardia was significantly decreased by NPY or [Leu31,Pro34]NPY in the methscopolamine-treated group. However, these changes in the baroreflex were no different from those elicted by equipressor doses of methoxamine. There was no vagal inhibition by any NPY-receptor agonist in all three autonomic reflexes examined. ACh or isoprenaline dose-HR response curves were not affected by NPY peptide administration. 4. We conclude that in the conscious rabbit, at a single dose that elicits a significant pressor response, exogenous NPY has no direct effect on modulation of cardiac and autonomic reflexes. Non-specific effects of exogenous NPY on the baroreflex may be fully explained by its pressor action. There was no effect of NPY on postjunctional ACh or isoprenaline agonist dose-response curves. Therefore, it is unlikely that endogenous NPY has a functional role in directly modulating cardiac autonomic neurotransmission in the rabbit.
Adrenergic beta-Agonists↗