Hindquarter Vascular Resistance Research Articles

Abstract 12867: Neuromodulation Of The Renal Nerves In Spontaneously Hypertensive Rats

Introduction: Hypertension is a global burden. Renal denervation has been touted as a possible therapeutic strategy for the treatment of hypertension. However, neuromodulation of the renal nerves’ traffic in hypertension has yet to receive a similar attention. Aim: This study investigated cardio-respiratory responses to renal nerve stimulation in a genetic model of hypertension, the spontaneously hypertensive rat (SHR). Methods: In pentobarbital-anesthetized male SHRs (n = 9), the left renal nerve was stimulated 5 times (5-6 minutes apart) at 5 Hz, 0.5 ms, 0.5 mA for 30s. Mean arterial pressure (MAP), heart rate (HR), left renal cortical blood flow (CBF) and cortical vascular resistance (CVR), hindquarter aortic blood flow (ABF) and vascular resistance (AVR), upper (UAP) and lower (LAP) airway pressure, airway flow (AF), airway resistance (AR), respiration rate (RR) and diaphragmatic EMG (dEMG) were measured and averaged. Results: Cardiovascular responses to renal nerve stimulation were characterized by reductions in MAP, HR, CBF and AVR, which were associated with increases in ABF and CVR. Respiratory responses to renal nerve stimulation, on the other hand, demonstrated increases in AF, RR and dEMG, decreases in AR and no change in UAP and LAP. Conclusions: Under hypertensive conditions, the renal nerves not only modulate cardiovascular function but also improve respiratory function. These studies suggest that neuromodulation of the renal nerves may offer a therapeutic alternative for hypertensive patients.

Abstract MP19: Endogenous 5-hydroxytryptamine May Regulate Skeletal Muscle Vascular Resistance In Normal Healthy Rats

Infusing low doses of 5-hydroxytryptamine (5-HT) into normal rats causes chronic (weeks to months) hypotension and a fall in total peripheral resistance. These effects are mediated by activation of 5-HT 7 receptors. Therefore, we generated 5-HT 7 receptor knockout rats (5-HT 7 KO) to explore possible cardiovascular effects of 5-HT 7 receptors under normal and pathophysiological conditions. We previously reported that healthy 5-HT 7 KO rats have normal blood pressure and total peripheral resistance at rest. This suggested that 5-HT 7 receptors plays no role in cardiovascular regulation under normal conditions. But total peripheral resistance is determined by multiple vascular beds that differ in their sensitivity to 5-HT. Others have indicated that 5-HT 7 receptors in the skeletal muscle vasculature are particularly sensitive to the effects of 5-HT. Therefore, we hypothesized that 5-HT 7 KO rats would show both reduced responsiveness to exogenous 5-HT and increased resting skeletal muscle vascular resistance. Experiments were performed in isoflurane-anesthetized, male Sprague-Dawley (SD) (n=6), 5-HT 7 wild-type (5-HT 7 WT) (n=5) and 5-HT 7 KO (n=6) rats at 7-8 months of age. Arterial pressure was measured with an aortic catheter. Blood flow to the hindquarters (mostly skeletal muscle) was measured with transit-time, ultrasound flowmetry. After 10 minutes of baseline hemodynamic measurements were obtained, 5-HT was infused iv at a rate of 25 μg/kg/min for 15 minutes, followed by a 15-minute recovery period. As expected, 5-HT 7 KO rats did not show a significant fall in hindquarter vascular resistance (HQVR) during 5-HT infusion, while SD and 5-HT 7 WT did. More importantly, HQVR at baseline was significantly (p < 0.05) higher in 5-HT 7 KO rats (16.0 ± 2.0 mmHg/ml/min) than in 5-HT 7 WT rats (10.9 ± 0.06 mmHg/ml/min) or SD rats (7.0 ± 0.03 mmHg/ml/min). These results support our hypothesis that in healthy (albeit anesthetized) rats, 5-HT 7 receptors reduce skeletal muscle vascular resistance.

Reduction in Hindquarter Vascular Resistance Supports 5-HT7 Receptor Mediated Hypotension.

The 5-HT7 receptor is the primary mediator of both the acute (<hours) and chronic (day-week) decreases in mean arterial pressure (MAP) during low dose 5-HT infusion in rats. Previous data show the hypotensive response during chronic 5-HT infusion is due to a decrease total peripheral resistance (TPR) and specifically splanchnic vascular resistance. We hypothesized that changes in vascular resistance in both the splanchnic and skeletal muscle vascular beds are critical to the cardiovascular effects mediated by the 5-HT7 receptor. Systemic and regional hemodynamic data were collected in conscious and anesthetized male rats using radiotelemetry, vascular catheters and transit-time flowmetry. Reversible antagonism of the 5-HT7 receptor was achieved with the selective antagonist SB269970 (33 μg/kg, iv). From the very beginning and throughout the duration (up to 5 days) of a low dose (25 μg/kg) infusion of 5-HT, TPR, and MAP were decreased while cardiac output (CO) was increased. In a separate group of rats, the contribution of the 5-HT7 receptor to the regional hemodynamic response was tested during 5-HT-induced hypertension. The decrease in MAP after 24 h of 5-HT (saline 83 ± 3 vs. 5-HT 72 ± 3 mmHg) was associated with a significant decrease in skeletal muscle vascular resistance (saline 6 ± 0.2 vs. 5-HT 4 ± 0.4 mmHg/min/mL) while splanchnic vascular resistance was similar in 5-HT and saline-treated rats. When SB269970 was administered acutely, MAP and skeletal muscle vascular resistance rapidly increased, whereas splanchnic resistance was unaffected. Our work suggests the most prominent regional hemodynamic response to 5-HT7 receptor activation paralleling the fall in MAP is a decrease in skeletal muscle vascular resistance.

Effects of intracerebroventricular injections of 5-HT on systemic vascular resistances of conscious rats

The aims of this study were to determine (i) the effects of intracerebroventricular (i.c.v.) injections of 5-hydroxytryptamine (5-HT, 10μg) on mean arterial blood pressure (MAP), heart rate (HR) and mesenteric (MR), renal (RR) and hindquarter (HQR) vascular resistances of conscious rats, (ii) the central 5-HT receptor subtype which mediates these effects, and (iii) the role of nitric oxide (NO) in the expression of these responses. The i.c.v. injection of 5-HT had minor effects on MAP but produced a decrease in HR (−18±4%), which lasted for 20min. The i.c.v. injection of 5-HT elicited marked increases in MR (+50±7%) and reductions in HQR (−31±3%). These responses occurred promptly and lasted for 25–35min. 5-HT also produced a transient decrease in RR (−26±8% at 10min). All of these responses were prevented by the prior i.c.v. injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (10μg). The intravenous injection of the NO synthesis inhibitor, L-NAME (25μmol/kg), produced a sustained pressor response, bradycardia and increases in MR, RR and HQR. Subsequent i.c.v. injection of 5-HT produced a minor pressor response (+7±2%), bradycardia (−18±3%), an increase in MR (+52±8%) but no decreases in RR or HQR. This study demonstrates that i.c.v. 5-HT differentially affects peripheral vascular resistances by activation of central 5-HT1/5-HT2-receptors. It appears that L-NAME did not interfere with the central actions of 5-HT as it did not prevent the 5-HT-induced bradycardia or mesenteric vasoconstriction. Since the 5-HT-induced falls in RR and HQR were abolished by L-NAME, it is possible that these responses are mediated by an active neurogenic process involving the release of NO within the vasculature.

Hemodynamic responses elicited by systemic injections of isotonic and hypertonic saline in hemorrhaged rats

PurposeThe objectives of this study were (i) to characterize the hemodynamic responses caused by controlled hemorrhage (HEM) in pentobarbital-anesthetized rats, and (ii) to determine the responses elicited by systemic bolus injections of isotonic saline (0.15M) or hypertonic saline (3M) given 5min after completion of HEM. ResultsControlled HEM (4.3±0.2ml/rat at 1.5ml/min) resulted in a pronounced and sustained fall in mean arterial blood pressure (MAP) to about 40mmHg. The fall in MAP was associated with a reduction in hindquarter vascular resistance (HQR) but no changes in renal (RR) or mesenteric (MR) vascular resistances. Systemic injections of isotonic saline (96–212μmol/kg i.v., in 250–550μl) did not produce immediate responses but promoted the recovery of MAP to levels below pre-HEM values. Systemic injections of hypertonic saline (750–3000μmol/kg, i.v., in 250–550μl) produced immediate and pronounced falls in MAP, RR, MR and especially HQR of 30–120s in duration. However, hypertonic saline prompted a full recovery of MAP, HQR and RR to pre-HEM levels and an increase in MR to levels above pre-HEM values. ConclusionsThis study demonstrates that (i) HEM induced a pronounced fall in MAP which likely involved a fall in cardiac output and HQR, (ii) isotonic saline did not fully normalize MAP, and (iii) hypertonic saline produced dramatic initial responses, and promoted normalization of MAP probably by restoring blood volume and cardiac output through sequestration of fluid from intracellular compartments.

Influence of nimodipine on vasoconstrictor responses in the hindquarters vascular bed of the cat.

The beneficial effects of the calcium-entry blocking agent, nimodipine, on the cerebral circulation have been extensively studied but less is known about its peripheral vascular effects. In the present study, the effects of nimodipine on vasoconstrictor responses were investigated in the hindquarters vascular bed of the cat under constant-flow conditions. Nimodipine decreased hindquarters vascular resistance and inhibited vasoconstrictor responses to BAY K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyr idine-5-carboxylate) and noradrenaline, to the alpha1-adrenoceptor agonists phenylephrine and methoxamine, and the alpha2-adrenoceptor agonists BHT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]azepine dihydrochloride) and UK 14304 (5-bromo-6-(2-imidazoline-2-yl-amino)quinoxaline). In addition to inhibiting alpha-adrenoceptor-mediated responses, nimodipine decreased responses to the vasoactive peptides angiotensin II and endothelin-1. Both the vasodilatory actions and inhibitory effects of nimodipine on vasoconstrictor responses were dose-dependent when the calcium antagonist was infused at rates of 0.1 and 1 microg min(-1). The results of the present study suggest that vasoconstrictor responses to alpha-adrenoceptor agonists and to the vasoactive peptides are dependent, in part, on an extracellular source of calcium. It is concluded that nimodipine and related dihydropyridine calcium-entry blocking agents may be effective in the treatment of peripheral vascular disorders in which adrenergic tone is increased or plasma levels of angiotensin II or endothelin-1 are elevated.

Hemodynamic Responses Elicited by Systemic Injections of Flavin Adenine Dinucleotide in Anesthetized Rats

Flavin adenine dinucleotide (FAD) elicits an endothelium-dependent vasodilation in isolated rat mesenteric beds via activation of P2Y-purinoceptors. The aims of this study were to characterize the hemodynamic responses elicited by systemic injections of FAD and flavin mononucleotide (FMN) in anesthetized rats and to determine the role of nitric oxide synthase (NOS), cyclooxygenase, P2Y/P2X-purinoceptors, and muscarinic receptor in these responses. FAD (0.05-1.0 micromol/kg, iv) elicited dose-dependent decreases in heart rate (HR), mean arterial blood pressure (MAP), and hindquarter vascular resistance (HQR), whereas it elicited an initial increase and then a decrease in mesenteric (MR) vascular resistance. The FAD-induced responses were not affected by the P2Y/P2X-purinoceptor antagonist suramin, the muscarinic receptor antagonist methyl-atropine, or the cyclooxygenase inhibitor indomethacin. The vasodilator actions of FAD were unaffected by the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME), whereas the bradycardia elicited by higher doses of FAD were diminished by L-NAME. FMN did not elicit hemodynamic responses in the absence or presence of L-NAME. In summary, FAD-induced bradycardia depends, in part, on the activation of NOS, whereas the vasodilator actions of FAD are not obviously due to newly synthesized nitrosyl factors. These findings and those in our companion manuscript support the concepts that the adenine moiety confers biological activity to FAD, which releases preformed pools of nitrosyl factors.

Hemodynamic Responses Elicited By γ 2-MSH or Blood Replacement in Hemorrhaged Rats

Systemic injections of compounds such as gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH), which increase sympathetic neurogenic vasoconstriction, may be beneficial in treating hemorrhage-induced hypotension. This study characterized (1) the hemodynamic responses elicited by systemic injections of gamma(2)-MSH in pentobarbital-anesthetized hemorrhaged rats, and (2) the hemodynamic responses elicited by the replacement of withdrawn blood in these rats. Controlled hemorrhage (4.8 +/- 0.3 mL/rat at 1.5 mL/min) resulted in a pronounced and sustained fall in mean arterial blood pressure (MAP). The fall in MAP was associated with a reduction in heart rate (HR) and hindquarter (HQR) vascular resistance but no changes in mesenteric (MR) or renal (RR) vascular resistances. Systemic injections of gamma(2)-MSH (10-40 microg/kg, i.v.) produced dose-dependent increases in HR, MAP, and vascular resistances of 20 to 60 s in duration in the hemorrhaged rats. In contrast, injection of the withdrawn blood produced an immediate and sustained increase in MAP, which was associated with a pronounced vasodilation in the hindquarter bed but no changes in MR or RR. These findings suggest that although gamma(2)-MSH elicits pressor and vasoconstrictor responses in hemorrhaged rats, the bolus injection of this peptide may not in itself be an effective strategy for the sustained restoration of MAP in these rats. Moreover, although blood replacement effectively restores MAP via increases in cardiac output rather than total peripheral resistance, it appears that this manipulation produces an active vasodilation in the hindquarter bed. The possibility that this vasodilation involves a sympathetic neurogenic vasodilator system, which innervates the hindlimb vascular bed but not mesenteric or renal vascular beds, will be discussed.

Involvement of central α 1- and α 2-adrenoceptors on cardiovascular responses to moxonidine

In the present study we compared the effects produced by moxonidine (α 2-adrenoceptor/imidazoline agonist) injected into the 4th cerebral ventricle and into the lateral cerebral ventricle on mean arterial pressure, heart rate and on renal, mesenteric and hindquarter vascular resistances, as well as the possible action of moxonidine on central α 1- or α 2-adrenoceptors to produce cardiovascular responses. Male Holtzman rats ( n = 7–8) anesthetized with urethane (0.5 g/kg, intravenously — i.v.) and α-chloralose (60 mg/kg, i.v.) were used. Moxonidine (5, 10 and 20 nmol) injected into the 4th ventricle reduced arterial pressure (− 19 ± 5, − 30 ± 7 and − 43 ± 8 mmHg vs. vehicle: 2 ± 4 mmHg), heart rate (− 10 ± 6, − 16 ± 7 and − 27 ± 9 beats per minute — bpm, vs. vehicle: 4 ± 5 bpm), and renal, mesenteric and hindquarter vascular resistances. Moxonidine (5, 10 and 20 nmol) into the lateral ventricle only reduced renal vascular resistance (− 77 ± 17%, − 85 ± 13%, − 89 ± 10% vs. vehicle: 3 ± 4%), without changes on arterial pressure, heart rate and mesenteric and hindquarter vascular resistances. Pre-treatment with the selective α 2-adrenoceptor antagonist yohimbine (80, 160 and 320 nmol) injected into the 4th ventricle attenuated the hypotension (− 32 ± 5, − 25 ± 4 and − 12 ± 6 mmHg), bradycardia (− 26 ± 11, − 23 ± 5 and − 11 ±6 bpm) and the reduction in renal, mesenteric and hindquarter vascular resistances produced by moxonidine (20 nmol) into the 4th ventricle. Pre-treatment with yohimbine (320 nmol) into the lateral ventricle did not change the renal vasodilation produced by moxonidine (20 nmol) into the lateral ventricle. The α 1-adrenoceptor antagonist prazosin (320 nmol) injected into the 4th ventricle did not affect the cardiovascular effects of moxonidine. However, prazosin (80, 160 and 320 nmol) into the lateral ventricle abolished the renal vasodilation (− 17 ± 4, − 6 ± 9 and 2 ± 11%) produced by moxonidine. The results indicate that the decrease in renal vascular resistance due to moxonidine action in the forebrain is mediated by α 1-adrenoceptors, while the cardiovascular effects produced by moxonidine acting in the brainstem depend at least partially on the activation of α 2-adrenoceptors.

Hemodynamic effects of combined treatment with oxygen and hypertonic saline in hemorrhagic shock*

In hemorrhagic shock, small volume resuscitation with hypertonic saline transiently increases mean arterial blood pressure (MABP) and cardiac output and augments organ perfusion. Inhalation of 100% oxygen after hemorrhage also increases MABP and redistributes blood flow to the splanchnic and renal vascular beds. We evaluated hemodynamic effects of combined resuscitation with hypertonic saline and oxygen in shock induced by controlled bleeding in rats. Animal study. Research laboratory. Male Sprague-Dawley rats. Animals were assigned to four hemorrhage groups that received posttreatment with a) normal saline; b) normal saline + 100% oxygen; c) hypertonic saline; d) hypertonic saline + oxygen, and a fifth sham-shock group that received hypertonic saline + oxygen. Bolus infusion of small volume hypertonic saline markedly increased MABP (p < .001), hindquarter vascular resistance (p < .05), and distal aorta blood flow (p < .01). Hypertonic saline transiently increased superior (cranial) mesenteric artery (SMA) blood flow (p < .001) and small bowel perfusion (p < .01). Inhalation of oxygen after normal saline rapidly increased MABP (p < .01) and hindquarter vascular resistance (p < .02) and decreased distal aorta blood flow (p < .02) and perfusion of the gracilis muscle (p < .05). When given after normal saline, oxygen did not change SMA resistance and increased SMA flow (p < .05). The supplementation of oxygen after hypertonic saline did not exert additional effects on vascular resistance and blood flows in the two vascular beds. However, the combined treatment prevented the oxygen-induced decrease in distal aorta blood flow and gracilis muscle perfusion and maintained MABP at slightly higher values and SMA flow at significantly higher values than hypertonic saline alone until the end of the protocol (p < .01). The two hemorrhaged groups treated with oxygen exhibited the lowest final plasma lactate concentrations (p < .05 from normal saline and hypertonic saline groups). We suggest that early combined use of hypertonic saline and oxygen exerts a favorable extended profile of hemodynamic effects that amends shortcomings of each treatment alone in hemorrhagic shock.

Antihypertensive Responses Elicited by Central Moxonidine in Rats: Possible Role of Nitric Oxide

In the present study, we investigated the effects of pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor) injected intravenously (IV) on the hypotension, bradycardia, and vasodilation produced by moxonidine (alpha2-adrenergic/imidazoline receptor agonist) injected into the fourth brain ventricle (4th V) in rats submitted to acute hypertension that results from baroreflex blockade by bilateral injections of kynurenic acid (kyn, glutamatergic receptor antagonist) into the nucleus of the solitary tract (NTS) or in normotensive rats. Male Wistar rats (n=5 to 7/group) anesthetized with IV urethane (1.0 g kg(-1) of body weight) and alpha-chloralose (60 mg kg(-1) of body weight) were used. Bilateral injections of kyn (2.7 nmol 100 nL(-1)) into the NTS increased baseline mean arterial pressure (148 +/- 11 mm Hg, vs. control: 102 +/- 4 mm Hg) and baseline heart rate (417 +/- 11 bpm, vs. control: 379 +/- 6 bpm). Moxonidine (20 nmol microL(-1)) into the 4th V reduced mean arterial pressure and heart rate to similar levels in rats treated with kyn into the NTS (68 +/- 9 mm Hg and 359 +/- 7 bpm) or in control normotensive rats (66 +/- 7 mm Hg and 362 +/- 8 bpm, respectively). The pretreatment with L-NAME (25 micromol kg, IV) attenuated the hypotension produced by moxonidine into the 4th V in rats treated with kyn (104 +/- 6 mm Hg) or in normotensive rats (95 +/- 8 mm Hg), without changing bradycardia. Moxonidine into the 4th V also reduced renal, mesenteric, and hindquarter vascular resistances in rats treated or not with kyn into the NTS and the pretreatment with L-NAME IV reduced these effects of moxonidine. Therefore, these data indicate that nitric oxide mechanisms are involved in hypotension and mesenteric, renal, and hindquarter vasodilation induced by central moxonidine in normotensive and in acute hypertensive rats.

L‐β,β‐Dimethylcysteine attenuates the haemodynamic responses elicited by systemic injections of peroxynitrite in anaesthetized rats

1 There is direct chemical evidence that L-beta,beta-dimethylcysteine (L-penicillamine (L-PEN)) is a scavenger of peroxynitrite. The aim of this study was to determine whether L-PEN attenuates the haemodynamic responses elicited by peroxynitrite in pentobarbital-anaesthetized rats. 2 Peroxynitrite (1-20 micromol kg(-1), i.v.) elicited dose-dependent reductions in mean arterial blood pressure (MAP) and mesenteric and hindquarter vascular resistances. 3 L-PEN (2 mmol kg(-1), i.v.) elicited relatively minor but significant increases in MAP and vascular resistances. The initial reductions in MAP and vascular resistances elicited by peroxynitrite were not diminished after administration of L-PEN whereas they were much shorter in duration. As such, the total reductions in MAP and vascular resistances were markedly reduced by L-PEN. 4 The finding that L-PEN (2 mmol kg(-1), i.v.) did not affect the hypotensive or vasodilator responses elicited of the ATP-dependent potassium-channel agonist, cromakalim (3-18 microg kg(-1), i.v.), suggests that this dose of L-PEN is not a nonselective inhibitor of vasodilation. 5 These findings suggest that L-PEN may effectively scavenge peroxynitrite in vivo and/or interfere with the mechanisms by which peroxynitrite elicits its vasodilator responses.

Lesions of the commissural nucleus of the solitary tract abolish the pressor response produced by CVLM deactivation.

A medullary circuitry involving the nucleus of the solitary tract (NTS) and the ventrolateral medulla (caudal and rostral) is essential to control the sympathetic discharge directed to the cardiovascular system. In the present study we sought to investigate the effects on mean arterial pressure (MAP), heart rate (HR) and regional vascular resistances produced by combining electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) and the deactivation of the caudal ventrolateral medulla (CVLM) with the GABAA agonist muscimol. Male Holtzman rats (n = 8/group) anesthetized with urethane (1.0 g/kg) + chloralose (60 mg/kg) iv were used. In sham rats, bilateral injections of muscimol (120 pmol) into the CVLM increased MAP (181 ± 6 mmHg, vs. control pre-injection: 104 ± 3 mmHg), HR (418 ± 16 bpm, vs. control pre-injection: 322 ± 12 bpm) and renal, mesenteric and hindquarter vascular resistances. However, in commNTS-lesioned rats, muscimol into the CVLM reduced MAP (67 ± 5 mmHg), HR (279 ± 8 bpm), renal, mesenteric and hindquarter vascular resistances below control baseline levels. The results suggest that important pressor mechanisms arise from the commNTS and CVLM to control vascular resistance and arterial pressure in the condition of the present study. Financial support: FAPESP, CNPq/PRONEX

Differential effects of nitroblue tetrazolium on the hemodynamic responses elicited by activation of α 1-adrenoceptors and 5-HT 2 receptors in conscious rats

This study determined the effects of the lipophobic electron acceptor, nitroblue tetrazolium (5 μmol/kg, i.v.) on the vasoconstrictor responses elicited by the 5-hydroxytryptamine 2 (5-HT 2) receptor agonist, α-methyl-5-HT (5–50 μg/kg, i.v.) and the α 1-adrenoceptor agonist, phenylephrine (2.5–20 μg/kg, i.v.) in conscious Sprague–Dawley rats. The systemic injection of nitroblue tetrazolium elicited pronounced hemodynamic responses that subsided by 10–15 min. Prior to the administration of nitroblue tetrazolium, the injections of α-methyl-5-HT and phenylephrine elicited dose-dependent increases in mean arterial blood pressure and mesenteric, renal and hindquarter vascular resistances. After administration of nitroblue tetrazolium, the vasoconstrictor responses elicited by α-methyl-5-HT were augmented whereas those elicited by phenylephrine were diminished. These results are consistent with the possibility that nitroblue tetrazolium interacts with the extracellular ligand-binding domains of 5-HT 2 receptors and α 1-adrenoceptor and that this interaction has opposite effects on activities of these G protein coupled receptors.

Role of ATP-Sensitive K+-Channels in Hemodynamic Effects of Peroxynitrite in Anesthetized Rats

The aim of this study was to determine whether the hypotensive and vasodilator actions of peroxynitrite in pentobarbital-anesthetized rats involve the activation of ATP-sensitive K+-channels (K+ATP-channels). The effects of the K+ATP-channel agonist, cromakalim (9-36 microg/kg, iv), peroxynitrite (0.5-10 micromol/kg iv), and L-S-nitrosocysteine (12.5-200 nmol/kg, iv) on mean arterial blood pressure (MAP) and mesenteric (MR) and hindquarter (HQR) vascular resistances were determined before and after injection of the K+ATP-channel blocker, glibenclamide (40 micromol/kg, iv). Cromakalim, peroxynitrite, and L-S-nitrosocysteine produced dose-dependent reductions in MAP, MR, and HQR. Administration of glibenclamide did not affect resting hemodynamic parameters but markedly attenuated the hemodynamic actions of cromakalim. The maximal falls in MAP and HQR produced by peroxynitrite were attenuated by glibenclamide whereas the maximal falls in MR were not affected. In addition, the duration of the hypotensive and vasodilator effects of peroxynitrite in the mesenteric and hindquarter beds were markedly diminished by glibenclamide. In contrast, glibenclamide did not affect the maximal hypotensive or vasodilator effects of L-S-nitrosocysteine or the duration of these responses. These results suggest that the hypotensive and vasodilator actions of peroxynitrite in anesthetized rats involve the activation of K+ATP-channels whereas the hemodynamic actions of L-S-nitrosocysteine do not.

Loss of K+ ATP-Channel-Mediated Vasodilation After Induction of Tachyphylaxis to Peroxynitrite

Systemic injections of peroxynitrite elicit pronounced vasodilator responses in rats by activation of ATP-dependent K+ channels (K+ATP-channels). The aim of this study was to determine whether development of tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function. The falls in mean arterial blood pressure (MAP) and mesenteric and hindquarter vascular resistances produced by the K+ATP-channel agonist, cromakalim (3-18 microg/kg, iv), and the nitric oxide (NO) donor, sodium nitroprusside (SNP; 1-4 microg/kg, iv), were determined in pentobarbital-anesthetized rats before and after induction of tachyphylaxis to peroxynitrite induced by the administration of 10 injections of peroxynitrite (10 micromol/kg, iv). The first dose of peroxynitrite elicited pronounced falls in MAP and vascular resistances whereas the tenth injection elicited much smaller responses that were equivalent to those of decomposed peroxynitrite. Before induction of tachyphylaxis to peroxynitrite, cromakalim and SNP produced dose-dependent reductions in MAP and vascular resistances. The hemodynamic actions of cromakalim were markedly attenuated after induction of tachyphylaxis to peroxynitrite whereas the SNP-induced responses were only slightly attenuated. These results suggest that tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function whereas tachyphylaxis to peroxynitrite minimally affects NO-mediated vasodilation. Taken together, these findings raise the possibility that peroxynitrite inhibits K+ATP-channel function by oxidation and/or nitration of amino acids in these channels.

Role of nitrosyl factors in the hindlimb vasodilation elicited by baroreceptor afferent nerve stimulation

This study determined whether electrical stimulation (ES) of the baroreceptor afferent fibers in the aortic depressor nerve (ADN) produces hindlimb vasodilation in pentobarbital-anesthetized rats via the release of nitric oxide (NO)-containing (nitrosyl) factors from NO synthase-positive lumbar sympathetic nerve terminals. ES of the ADN (1-10 Hz for 15 s) produced frequency-dependent reductions in mean arterial blood pressure (MAP) and mesenteric and hindlimb vascular resistance (MR and HLR, respectively). The falls in resistance were substantially smaller in hindlimb beds in which the ipsilateral lumbar sympathetic chain had been transected 7-10 days previously. The maximal falls in MR and hindquarter vascular resistance (HQR) produced by 1- to 10-Hz ES of the ADN were unaffected by the specific inhibitor of neuronal NO synthase 7-nitroindazole (7-NI, 45 mg/kg iv). However, the total falls in HQR (mmHg.kHz(-1).s) produced by these stimuli were significantly diminished by 7-NI, whereas the total falls in MR were not affected. Four successive episodes of 10-Hz ES produced equivalent reductions in MAP, MR, and HQR. The peak changes in these parameters were not affected by 7-NI. However, the total falls in HQR progressively diminished with each successive stimulus, whereas the total falls in MR remained unchanged. These results provide evidence that the hindlimb vasodilation produced by ES of baroreceptor afferents within the ADN may involve the activation of postganglionic lumbar sympathetic vasodilator fibers, which release newly synthesized and preformed nitrosyl factors.

Role of pressor mechanisms from the NTS and CVLM in control of arterial pressure

In the present study, we investigated the effects of inhibition of the caudal ventrolateral medulla (CVLM) with the GABA(A) agonist muscimol combined with the blockade of glutamatergic mechanism in the nucleus of the solitary tract (NTS) with kynurenic acid (kyn) on mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances. In male Holtzman rats anesthetized intravenously with urethane/chloralose, bilateral injections of muscimol (120 pmol) into the CVLM or bilateral injections of kyn (2.7 nmol) into the NTS alone increased MAP to 186 +/- 11 and to 142 +/- 6 mmHg, respectively, vs. control: 105 +/- 4 mmHg; HR to 407 +/- 15 and to 412 +/- 18 beats per minute (bpm), respectively, vs. control: 352 +/- 12 bpm; and renal, mesenteric and hindquarter vascular resistances. However, in rats with the CVLM bilaterally blocked by muscimol, additional injections of kyn into the NTS reduced MAP to 88 +/- 5 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Moreover, in rats with the glutamatergic mechanisms of the NTS blocked by bilateral injections of kyn, additional injections of muscimol into the CVLM also reduced MAP to 92 +/- 2 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Simultaneous blockade of NTS and CVLM did not modify the increase in HR but also abolished the increase in renal vascular resistance produced by each treatment alone. The results suggest that important pressor mechanisms arise from the NTS and CVLM to control vascular resistance and arterial pressure under the conditions of the present study.

Lesions of the anteroventral third ventricle region (AV3V) disrupt cardiovascular responses to an elevation in core temperature

Blood flow is redistributed from the viscera to the periphery during periods of heat stress to maximize heat loss. The heat-induced redistribution of blood flow is strongly influenced by nonthermal inputs such as hydration status. At present, little is known about where thermal and nonthermal information is integrated to generate an appropriate effector response. Recently, the periventricular tissue that surrounds the anteroventral third ventricle (AV3V) has been implicated in the integration of thermal and osmotic information. The purpose of the present study was to determine the effects of electrolytic lesions of the AV3V on the cardiovascular response to a passive heat stress in unanesthetized, free-moving male Sprague-Dawley rats. Core temperature was elevated at a constant rate of approximately 0.03 degrees C/min in sham- and AV3V-lesion rats using an infrared heat lamp. Changes in mesenteric and hindquarter vascular resistance were determined using Doppler flow probes, and heat-induced salivation was estimated using the spit-print technique. The rise in mean arterial pressure (MAP), heart rate (HR), and mesenteric resistance in response to elevations in core temperature were all attenuated in AV3V-lesion rats; however, hindquarter resistance was unaffected. Heat-induced salivation was also diminished. In addition, AV3V-lesion rats were more affected by the novelty of the experimental environment, resulting in a higher basal core temperature, HR, and MAP. These results indicate that AV3V lesions disrupt the cardiovascular and salivatory response to a passive heat stress in rats and produce an exaggerated stress-induced fever triggered by a novel environment.

Effects of selective dopamine receptor subtype agonists on cardiac contractility and regional haemodynamics in rats

1. Activation of dopamine (DA) receptors produces cardiovascular responses such as vasodilation and hypotension. However, knowledge of the role of specific dopamine receptor subtypes (especially D3 and D4) in the cardiovascular system is limited. The objective of the present study was to characterize the haemodynamic and cardiac responses to agonists with selectivity for D1, D2, D3 and D4 receptor subtypes. 2. Inactin-anaesthetized rats were instrumented to measure regional haemodynamic and cardiac contractility responses with slow intravenous infusion of agonists. 3. Fenoldopam (a D1 receptor agonist) decreased (P < 0.05) renal vascular resistance beginning at a dose of 3 micromol/kg. Infusion of PNU-95666E (a D2 receptor agonist) produced dose-dependent decreases (P < 0.05) in mean arterial pressure (MAP), heart rate (HR) and hindquarter vascular resistance (HQVR). Administration of BP897 (a partial D3 receptor agonist) decreased (P < 0.05) MAP and HQVR at 3 micromol/kg. PD168077 (a D4 receptor agonist) caused significant increases in HQVR at 1 micromol/kg. None of the compounds tested elicited significant changes in cardiac contractility. 4. Using selective agonists of dopamine receptor subtypes, the present studies characterize distinct cardiovascular effects in anaesthetized rats. Consistent with its well-defined effects as a D1 receptor agonist, fenoldopam administration resulted in renal vasodilation. Similar to earlier studies using the non-selective D2-like receptor agonist quinpirole, selective agonism at the D2 receptor using PNU-95666E resulted in bradycardia, hindquarter vasodilation and decreases in arterial pressure. Partial agonism at the D3 receptor with BP897 had no effect on heart rate, but did produce depressor responses driven by decreases in HQVR. Conversely, agonism of the D4 receptor using PD168077 resulted in modest hindquarter vasoconstriction that was not dose dependent. Hence, by comparison, agonism of the D4 receptor has little effect in the cardiovascular system of the rat relative to the other dopamine receptor subtype agonists tested.