Potentiation Of Pressor Response Research Articles

Sensory Neuron Sensitization By Pkc-induced Trpv1 Phosphorylation In Type 2 Diabetic Rats

Skeletal muscle reflex-induced increases in blood pressure are exaggerated during exercise in type 2 diabetes mellitus (T2DM). We previously demonstrated that skeletal muscle afferent discharge in response to capsaicin, a transient receptor potential cation channel subfamily V member 1 (TRPV1) agonist, is heightened in T2DM likely contributing to the potentiated pressor response. However, the underlying mechanisms remain unclear. Evidence suggests that the high glucose levels in T2DM sensitize sensory neurons through the receptor for advanced glycation end products (RAGE)/protein kinase C (PKC) pathway in dorsal root ganglia (DRG). Moreover, early-stage diabetes associated with TRPV1 overactivity is mediated through PKC. Therefore, it was hypothesized that the augmentation in muscle afferent discharge in T2DM previously reported is due to the phosphorylation of TRPV1 via an overactive RAGE/PKC pathway. PURPOSE: To investigate 1) the impact of T2DM on plasma levels of advanced glycation end products (AGE) and high-mobility group box-protein 1 (HMGB-1), both RAGE ligands, and 2) the impact of T2DM on the RAGE/PKC pathway including the phosphorylation of TRPV1 in DRG subserving skeletal muscle afferents. METHODS: For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or a high fat diet in combination with a low dose (35 mg/kg) of streptozotocin (T2DM). Plasma insulin, HMGB1 and AGE were determined using ELISA. RAGE, phosphorylated PKC and TRPV1 protein levels were quantified in DRG by western blotting. RESULTS: After overnight fasting, T2DM rats exhibited hyperglycemia (95±6 vs. 156±18 mg/dL, P<0.05) and hyperinsulinemia (1.6±0.2 vs. 4.1±0.4 ng/mL, P<0.05). HMGB1, AGE and RAGE did not differ between groups. Phosphorylated PKC (1.0±0.1 vs. 1.2±0.2 arb unit, P=0.08) and TRPV1 (1.0±0.3 vs. 1.3±0.4 arb unit, P=0.08) levels in DRG tended to be greater in T2DM than control. CONCLUSIONS: These findings suggest that phosphorylated TRPV1 may be increased by PKC overactivity in DRG of T2DM but acts independently of RAGE. Importantly, these changes may mediate the sensitization of skeletal muscle afferents facilitating the exaggerated pressor response to exercise characteristic of T2DM. Supported by Lawson & Rogers Lacy Research Fund and SHP Interdisciplinary Research Grant Program.

Skeletal Muscle Reflex-Induced Sympathetic Dysregulation and Sensitization of Muscle Afferents in Type 1 Diabetic Rats.

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; P<0.05), mechanoreflex (21±13 versus 51±20%; P<0.05), and metaboreflex (40±20 versus 88±39%; P<0.01) activation in T1DM rats evoked significant increases in renal sympathetic nerve activity as well as mean arterial pressure. The response of group IV afferents to mechanical (18±24 versus 61±45 spikes; P<0.01) and chemical (0.3±0.4 versus 1.6±0.8 Hz; P<0.01) stimuli were significantly greater in T1DM than control. T1DM rats showed markedly increased pPKCα levels in dorsal root ganglia compared with control. These data suggest that in T1DM, abnormally muscle reflex-evoked increases in sympathetic activity mediate exaggerations in blood pressure. Further, sensitization of muscle afferents, potentially via PKC activation, may contribute to this abnormal circulatory responsiveness.

Ebselen prevents the carotid body chemosensory potentiation and reverses the hypertension induced by intermittent hypoxia (873.1)

Oxidative stress is associated with hypertension and enhanced carotid body (CB) chemosensory responses induced by chronic intermittent hypoxia (CIH), but the underlying mechanism is not fully understood. We tested if ONOO‐ is involved in the CB enhanced chemosensivity. Accordingly, we studied the effects of Ebselen, a specific ONOO‐ scavenger, on 3‐nitrotirosine immunoreactivity (3‐NT‐ir) in the CB, the chemosensory discharge and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague‐Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day), BP was measured with telemetry and Ebselen was administrated using subcutaneous osmotic pumps (10 mg/Kg day). At the end of the experiments, CB chemosensory discharge was recording, and rats were perfused with parafolmaldehyde 4% for 3‐NT‐ir. CIH increased 3‐NT‐ir in the CB, enhanced the chemosensory responses to hypoxia, elevated BP during normoxia and potentiated the BP responses to hypoxia. Ebselen prevented the CIH‐induced CB chemosensory potentiation, and reversed the elevated BP and the potentiated pressor responses to hypoxia. Our results showed that 3‐NT formation caused by CIH, contributes to the CB chemosensory potentiation, and that ONOO‐ is involved in the CIH‐induced hypertension.Grant Funding Source: Supported by FONDECYT 1100405

PAI-1-Derived Peptide EEIIMD Prevents Hypoxia/Ischemia-Induced Aggravation of Endothelin- and Thromboxane-Induced Cerebrovasoconstriction

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole FDA approved treatment for acute stroke is tissue-type plasminogen activator (tPA). Endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after H/I in pigs. Mitogen-activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to impaired vasodilation. This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK. Cerebral hypoxia (pO(2) 35 mmHg for 10 min via inhalation of N(2)) followed immediately by ischemia (global intracranial pressure elevation for 20 min) was produced in chloralose anesthetized piglets equipped with a closed cranial window. H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimetic U 46619. Potentiated vasoconstrictor responses were blocked by EEIIMD, an inhibitor of tPA's signaling and vascular activities, but unchanged by its inactive analogue EEIIMR. The cerebrospinal fluid concentration of ERK MAPK determined by ELISA was increased by H/I, potentiated by tPA, but blocked by EEIIMD. The ERK MAPK antagonist U 0126 blocked H/I augmented enhancement of ET-1 and U 46619 vasoconstriction. These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction by upregulating endogenous tPA and ERK MAPK.

Effects of White Mulberry (Morus alba) Leaves on Blood Vessel Reactivity in Hyperchloesterolemic Rats

동맥경화 상태에서는 혈관이 수축물질에 예민하게 반응함으로써 혈압의 급격한 변화에 대한 회복능력이 저하한다. 한편 뽕나무 잎에는 고지방식의 섭취로 인해 발생하는 동맥경화증의 발달을 감소시킬 가능성이 있는 여러 물질이 있다고 추정된다. 뽕나무 잎을 백서에 투여하면 고지방식에 의해 유발된 혈관이 예민해지는 현상을 감소시킬 수 있는지 시험하기 위하여 고지방식 및 뽕나무잎을 8주간 투여하고 혈관수축 물질에 대한 혈압의 반응성을 시험하였다. 순환기반사에 따른 혈압반응 감수성차이를 최소화할 목적으로 동물의 중추신경계를 파괴(pithing)하고 시험하였다. 고콜레스테롤을 함유한 식이를 공급한 백서에서 교감신경계 전기자극이나 norepinephrine, phenylephrine, angiotensin II 및 vasopressin 등의 투여로 유발된 혈압상승반응이 증강되었으며, 사료에 뽕잎을 2% 또는 10% 첨가하면 정상적인 혈압상승반응을 보여주었다. 교감신경계를 파괴하지 않은 채 마취만 한 백서에서는 고콜레스테롤에 의한 반응증강이나 뽕잎에 의한 변화를 관찰할 수 없었다. 이 결과로 부터 뽕잎이 동맥경화에서 나타나는 혈관반응성 변화를 방지하는 데 유용한 것으로 판단할 수 있을 것이다. In atherosclerosis, blood vessels become sensitive to vessel-constricting agents leading to reduced control in the event of abrupt blood pressure changes. Mulberry trees (Morus alba L., MA) have been claimed to contain various bioactive principles that could possibly prevent atherosclerosis development caused by high cholesterol consumption. In order to examine whether MA feeding can prevent the sensitization of blood vessels, MA leaves were fed to rats for 8 weeks and pressor responses to vasoconstricting agents were assessed. Animals were pithed before blood pressure assessments to eliminate reflex compensation in vessel responses. Feeding diets containing high levels of cholesterol led to potentiated pressor responses to sympathetic nerve stimulation, or to injection of norepinephrine, phenylephrine, angiotensin II and vasopressin in pithed rats. These potentiated pressor responses were prevented in rats fed MA leaf-containing diets at 2 or 10% levels. It was also examined in anesthetized non-pithed rats whether similar cholestrol-related sensitization and MA prevention could be observed. However, high cholesterol-induced sensitization in pressor responses were not observed, suggesting that destruction of central cardiovascular control by pithing must have revealed the sensitization responses. It was concluded that MA leaves seem to be active in preventing abnormal blood vessel reactivity caused by hypercholesterolemia.

Effect of acute and chronic treatment with practolol on cardiovascular responses in the pithed rat.

Abstract Chronic administration of practolol to the pithed rat produced a reduction in the pressor responses to electrical stimulation of the spinal cord and potentiation of pressor responses to high doses of (—)-noradrenaline compared to control animals. Acute administration of practolol caused an increase in the pressor responses to both electrical stimulation and high doses of noradrenaline. Heart rate responses to both forms of stimulation were less than control values after both acute and chronic dosage with practolol. It is possible that practolol reduces the release of noradrenaline at the sympathetic nerve ending after chronic administration.

Augmented Potentiation of Renal Vasoconstrictor Responses by Thromboxane A2 Receptor Stimulation in the Alloxan-diabetic Rat

Dose-response curves were obtained to bolus injections of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in blood and Krebs-perfused kidneys of male Wistar rats. Vasoconstrictor responses to both NA and 5-HT were significantly attenuated in blood-perfused kidneys of alloxan-treated 14 day diabetic rats compared with non-diabetic animals. Responses to low doses of NA were also significantly attenuated in Krebs-perfused kidneys from diabetic rats but responses to 5-HT were augmented. Dose-dependent potentiation of vasoconstrictor responses to NA and 5-HT in Krebs-perfused kidneys of both non-diabetic and diabetic rats occurred during infusion of the thromboxane A2 (TxA2)-mimetic U46619 [15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid). The potentiation by U46619 (11 ng mL-1) was inhibited in both groups during infusion of the thromboxane receptor antagonist AH23848 [( 1 alpha(Z), 2 beta, 5 alpha]-(+/-)-7-[5[[(1,1'-biphenyl)-4-yl]methoxyl]-2-(4- morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). Infusion of 5-HT in Krebs-perfused kidneys of non-diabetic rats, causing a rise in perfusion pressure of similar magnitude to that produced by infusion of 111ng mL-1 U46619, did not significantly affect responses to bolus injections of NA. Potentiation of vasoconstrictor responses to low concentrations of 5-HT by U46619 was significantly greater in Krebs-perfused kidneys of diabetic rats than kidneys from non-diabetic animals. Activation of vascular TxA2 receptors augments the vasoconstrictor effects of 5-HT in Krebs-perfused diabetic rat kidneys to a greater extent than in non-diabetic kidneys.

Seasonal Influence on Insulin and Cortisol Results from Overnight Dexamethasone Suppression Tests (DST) in Normal and Previously Laminitic Ponies

Seasonal Influence on Insulin and Cortisol Results from Overnight Dexamethasone Suppression Tests (DST) in Normal and Previously Laminitic Ponies

Modulation of Endothelium-Dependent Relaxation of Equine Digital Arteries By Insulin and Hypoxia

Modulation of Endothelium-Dependent Relaxation of Equine Digital Arteries By Insulin and Hypoxia

Endothelial Function in the Time of the Giants

Paul Vanhoutte is one of the fathers of vascular biology. Among his great contributions, he demonstrated that endothelium modulates vasomotor response to vasoactive products (including serotonin) that are released when platelets aggregate in an artery. He found in arteries ex vivo that when endothelium is dysfunctional, in atherosclerosis or hypertension, normal relaxation to aggregation of platelets is impaired and vessels may contract. He proposed that this mechanism may predispose to vasospasm. The results of our experiments in vivo indicate that atherosclerosis greatly potentiates vasoconstrictor responses to serotonin in the limb, brain, and eye of monkeys. We proposed that transient ischemic attacks may be mediated by platelet-induced vasospasm. We observed endothelial dysfunction in atherosclerotic monkeys, with improvement of endothelial function when hypercholesterolemia was corrected. Recently, we studied the aortic valve, which has unique endothelium, in hypercholesterolemic mice to examine the pathophysiology of aortic valvular stenosis. Oxidative stress is increased in stenotic valves, and severe aortic stenosis develops in about one third of old, hypercholesterolemic mice. In stenotic aortic valves from humans, there is increased oxidative stress near calcified regions of the valves. Oxidative stress may trigger expression of pro-calcific genes in the aortic valve. Finally, we have used gene transfer of extracellular superoxide dismutase (ecSOD) to study endothelial effects of oxidative stress. Gene transfer of normal ecSOD improves endothelial dysfunction in several disease states, but gene transfer of ecSOD(R213G), a gene variant of ecSOD that is common in humans, fails to improve endothelial function. Gene transfer approaches may be useful to study mechanisms by which gene variants predispose to endothelial dysfunction and vascular disease.

Assessment of endothelium‐dependent vasodilation in equine digital resistance vessels

Haemodynamic disturbances leading to ischaemia and reperfusion injury of the digit are thought to be involved in the pathophysiology of acute equine laminitis. Identification of physiological regulators of blood flow through the equine digit is important in identifying factors, which may predispose animals to laminitis. A method was developed to assess endothelium-dependent responses of the isolated Krebs-perfused equine digit by co-administration of 5-hydroxytryptamine (5-HT) with vasodilator agents, carbachol (CCh), bradykinin (BK) and substance P (SP). Bolus co-administration of CCh (0.02-2 micromol), BK and SP (0.02-0.2 nmol), caused inhibition of the 5-HT pressor response by 50-60%. The vasodilator responses were abolished by the detergent, CHAPS, indicating endothelium dependency; whereas vasoconstrictor responses to 5-HT were potentiated. CCh-induced relaxation was significantly reduced by the nitric oxide synthase inhibitor L-NAME (79.7 +/- 3.4% inhibition), whereas a large proportion of BK and SP-induced relaxation remained (34.1 +/- 6.3% and 33.6 +/- 5.3% inhibition). L-NAME potentiated vasoconstrictor responses to 5-HT. In conclusion, this study demonstrates that endothelium-derived NO modulates the response to vasoconstrictors such as 5-HT and is likely to be an important regulator of blood flow in the digital resistance vascular bed. Other factor(s) released by the endothelium are also important in regulating blood flow, whose identity remains to be established.

Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox)

Chronic exposure to low-O2 tension induces pulmonary arterial hypertension (PAH), which is characterized by vascular remodeling and enhanced vasoreactivity. Recent evidence suggests that reactive oxygen species (ROS) may be involved in both processes. In this study, we critically examine the role superoxide and NADPH oxidase plays in the development of chronic hypoxic PAH. Chronic hypoxia (CH; 10% O2 for 3 wk) caused a significant increase in superoxide production in intrapulmonary arteries (IPA) of wild-type (WT) mice as measured by lucigenin-enhanced chemiluminescence. The CH-induced increase in the generation of ROS was obliterated in NADPH oxidase (gp91phox) knockout (KO) mice, suggesting that NADPH oxidase was the major source of ROS. Importantly, pathological changes associated with CH-induced PAH (mean right ventricular pressure, medial wall thickening of small pulmonary arteries, and right heart hypertrophy) were completely abolished in NADPH oxidase (gp91phox) KO mice. CH potentiated vasoconstrictor responses of isolated IPAs to both 5-hydroxytryptamine (5-HT) and the thromboxane mimetic U-46619. Administration of CuZn superoxide dismutase to isolated IPA significantly reduced CH-enhanced superoxide levels and reduced the CH-enhanced vasoconstriction to 5-HT and U-46619. Additionally, CH-enhanced superoxide production and vasoconstrictor activity seen in WT IPAs were markedly reduced in IPAs isolated from NADPH oxidase (gp91phox) KO mice. These results demonstrate a pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH.

Role of endothelium-dependent mechanism in formation of systemic hemodynamic responses to hypervolemia.

Blockade of NO synthesis in anesthetized rats significantly potentiated pressor responses to Polyglucin (by 70%) and considerably increased total peripheral resistance. It was concluded that vasodilatation induced by increased systemic blood flow (cardiac output) modulates pressor responses under conditions of increased blood volume.

Potentiation of vasoconstrictor response and inhibition of endothelium-dependent vasorelaxation by gallic acid in rat aorta.

In the isolated rat thoracic aorta, gallic acid potentiated the vasoconstrictor response to phenylephrine. The potentiation produced by gallic acid was absent in endothelium-denuded arteries. The potentiation was abolished by N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, and slightly attenuated by an addition of L-arginine, while indomethacin or BQ610 had no effect. The potentiation of response to phenylephrine was not found for structural modifications of gallic acid, except for caffeic acid. Gallic acid also inhibited vasorelaxation induced by acetylcholine, sodium nitroprusside or prostacyclin, especially that by acetylcholine. The effect on vasorelaxation induced by acetylcholine was decreased by esterification of the carboxy group of gallic acid, and in the absence or by the methylation of the o-dihydroxy group. Caffeic acid inhibited the vasorelaxation, though the effect was smaller than that of gallic acid. These findings indicate that gallic acid produces a potentiation of contractile response and inhibition of vasorelaxant responses, probably through inactivation of nitric oxide (NO), in which endothelially produced NO is principally involved, and that the modification of functional groups of the gallic acid molecule abolishes the potentiation of contractile response and attenuates the inhibition of vasorelaxant responses.

Contractile effects of tacrolimus in human and rat isolated renal arteries.

1. We tested the vasoactive properties of the immunosuppressive drug FK 506 (tacrolimus) in preconstricted rat and human isolated renal arteries in vitro. 2. In rat renal arteries, tacrolimus (3, 10 microM) showed a direct and dose-dependent contractile effect by maximally 23 microm (10% of the noradrenaline effect), which was only observed in the presence of intact endothelium. Moreover, a lower concentration of tacrolimus (1 microM) potentiated pressor responses to the sympathetic neurotransmitter noradrenaline but not to ATP in this species. ATP- (0.01-10 microM) induced vasodilation was not affected by tacrolimus (1 microM). 3. In contrast, in human interlobar arteries, tacrolimus failed to induce direct vasoconstriction and did not significantly potentiate constrictor responses to noradrenaline. Acetylcholine-(1 microM) induced vasodilation was much smaller in human than in rat renal arteries suggesting the lack of functional endothelium in the human preparation. 4. The findings suggest that tacrolimus releases an endothelium-derived constricting factor in rat renal arteries to increase vascular tone and to potentiate pressor responses to noradrenaline. In human interlobar arteries, this effect of tacrolimus is not observed probably because of the absence of functional endothelium or the necessary mediator mechanism.

Enhanced blood pressure buffering role of the brain nitrergic system in renin transgenic rats

Previous studies provided evidence for an interaction between the brain nitrergic and vasopressinergic systems in normotensive and spontaneously hypertensive rats in regulation of the cardiovascular functions. The present study was designed to determine the role of the brain nitric oxide (NO) in regulation of basal blood pressure and its interaction with vasopressin (AVP) in rats with renin dependent transgenic hypertension TGRmRen2(27) (TGR). The experiments were performed on conscious hypertensive TGR and normotensive Sprague–Dawley (SD) rats. Both groups were chronically instrumented with the left cerebral ventricle cannula (LCV) and femoral arterial catheter. LCV application of 2.3 nmol (0.5 μg) of N G-nitro- l-arginine ( l-NNA) an inhibitor of NO synthesis significantly elevated blood pressure (MAP) in TGR but not in SD rats. In contrast administration of NO donor S-acetyl- N-penicillamine (SNAP) produced significant decrease of MAP only in SD rats. LCV application of AVP (10 ng) elicited comparable increases of MAP in TGR and SD rats. Pretreatment with l-NNA significantly potentiated pressor response to AVP in TGR rats but not in SD rats. The results provide evidence that increased production of intrabrain NO may play a significant blood pressure buffering role in TGR rats both under baseline conditions and during activation of the vasopressinergic system.

Effects of 4-Methyl-2-aminopyridine on [ 3H]-Noradrenaline Overflow and Contractility of Isolated Rabbit Arteries

1. The effects of 4-methyl-2-aminopyridine (4M2AP) and 4-aminopyridine (4AP) on spontaneous and evoked [ 3H]-noradrenaline overflow were compared in rabbit ear artery strips. The effects of 4M2AP on smooth muscle contractility were also investigated in isolated perfused ear arteries. 2. Both 4M2AP and 4AP enhanced spontaneous [ 3H] overflow from arterial strips in a concentration-dependent manner (10–1000 μM). A bell-shaped dose-response relation was obtained for evoked [ 3H] overflow over the same concentration range, with maximum effects occurring at 10 μM for 4M2AP (163±31% increase) and 100 μM for 4AP (154±16% increase). 3. 4M2AP did not significantly affect evoked tension in the 1- to 100-μM range but clearly depressed it at 1,000 μM (by 65±11%). In contrast, 4AP enhanced evoked tension in the 10- to 100- μM range (by 30–50%). 4. 4M2AP (10–100 μM) enhanced vasoconstrictor responses to exogenous noradrenaline injections in isolated perfused rabbit ear arteries, whereas higher concentrations (1,000 μM) caused significant depression. 5. 4M2AP (1,000 μM) markedly potentiated vasoconstrictor responses induced by perfusion with a high extracellular K + solution. When 4M2AP was present during the reloading of noradrenaline-sensitive Ca 2+ stores, it enhanced the subsequent vasoconstrictor responses to noradrenaline obtained in a Ca 2+-free medium. 6. The results show that 4M2AP, like 4AP, enhances [ 3H] overflow from sympathetic nerve terminals and has complex effects on vascular smooth muscle contractility, indicating the ability of these compounds to affect the Ca 2+ permeability of both extracellular and intracellular membrane systems.

Synergistic vascular effects of dietary sodium supplementation and angiotensin II administration.

The hypertensinogenic action of dietary sodium supplementation was investigated in angiotensin II (ANG II)-treated rats. We hypothesized that high-sodium diet would potentiate ANG II-induced vasoconstriction and hypertension, including the development of structural vascular changes, through synergistic action with ANG II in stimulating sympathetic activity and vascular growth. Mesenteric vasoconstrictor responses to ANG II, norepinephrine (NE), arginine vasopressin (AVP), and periarterial nerve stimulation were measured in Sprague-Dawley rats after 7-10 days of the following treatments: 200 ng.kg-1.min-1 ip ANG II (n = 12), 4% NaCl diet (n = 11), ANG II + 4% NaCl diet (n = 7), and 0.7% NaCl diet (controls) (n = 15). Additional rats received 50 ng.kg-1.min-1 sc ANG II (n = 8), 2% NaCl diet (n = 9), ANG II + 2% NaCl diet (n = 6), or 0.7% NaCl diet (controls) (n = 10) for 12 wk. Systolic blood pressure (SBP) values were measured weekly for 4 wk and then every other week for 8 wk. Then, the wall-to-lumen ratio (W/L) of mesenteric resistance arteries (< 150 microns OD) was measured after in situ perfusion-fixation. After 7-10 days of treatment, there were no significant changes in SBP in any of the groups. High-sodium diet increased vasoconstrictor responses to ANG II (P < 0.01) and nerve stimulation (P < 0.02), but not to NE or AVP, and in combination with ANG II treatment further potentiated vasoconstrictor responses to ANG II (synergism). After 12 wk of treatment, ANG II increased W/L of small resistance arteries by 11% (P < 0.05) without a significant rise in SBP. ANG II and 2% NaCl diet in combination raised SBP by 36 mmHg (P < 0.01) and increased small artery W/L by 28% (P < 0.001) compared with values obtained in control rats. To test the specificity of the interaction between ANG II and high-sodium diet, all the experiments were repeated during phenylephrine (PE, 10 micrograms.kg-1.min-1 sc) treatment of rats. PE by itself or in combination with high-sodium diet had no effect on the measured parameters. Thus short-term administration of high-sodium diet appears to potentiate vasoconstrictor responses to ANG II by facilitating sympathetic neurotransmission, and long-term administration of high-sodium diet raises SBP by potentiating the trophic vascular effects of ANG II. The interaction appears to be specific to ANG II and is occurring on the vascular level.

Different Vascular Responses to Subpressor Angiotensin II Administration in the Mesenteric and Renal Circulation of Rats

Administered in small doses, angiotensin II (ANG II) potentiates its own pressor responses (autopotentiation). In the present study, we investigated whether potentiation of vasoconstrictor responses in the mesenteric and renal circulation accounted for the autopotentiation of pressor responses. Male Sprague-Dawley rats, 350 to 400 g, were infused with 200 ng/kg/min ANG II intraperitoneally for 7 to 10 days. Control rats were fitted with an osmotic minipump containing vehicle only. Vascular responses to ANG II, norepinephrine (NE), arginine vasopressin (AVP) and nerve stimulation were measured in the mesenteric and renal circulation of rats. In ANG II-treated rats: 1) tail systolic BP was 4 mm Hg higher than in controls (P = NS); 2) mesenteric vascular responses to ANG II (P < .002) and nerve stimulation (P = .03) were increased, and those to NE and AVP were unchanged; and 3) renal vascular responses to nerve stimulation were reduced (P < .02), and those to ANG II, NE, and AVP were unchanged. Thus, we demonstrated autopotentiation of vascular responses to ANG II in the mesenteric, but not the renal circulation. An interaction between ANG II and sympathetic activity may explain these differences in regional vascular responses. Regional hemodynamic measurements may provide important clues to pathogenetic mechanisms in hypertension.

Nω-Nitro-L-arginine, an inhibitor of nitric oxide synthesis, increases blood pressure in rats and reverses the pregnancy-induced refractoriness to vasopressor agents

With N omega-nitro-L-arginine, a potent inhibitor of nitric oxide synthesis, we tested the hypothesis that nitric oxide plays a functional role in the blunted pressor responsiveness seen during pregnancy. A group of six pregnant rats were instrumented on the fourteenth day of gestation and studied on days 19 and 20, as well as 7 days post partum. Another group of six virgin rats were similarly prepared and used 5 days after surgery. Blood pressure and heart rate were monitored in conscious freely moving animals before and during the administration of drugs or placebo. Results were analyzed, by one-way repeated-measures analysis of variance, with Dunnett's t test, or by paired t test where applicable. Basal mean arterial pressure and heart rate were 90.8 +/- 3.0 mm Hg and 330 +/- 6 beats/min in pregnant animals and 107.1 +/- 3.2 mm Hg and 315 +/- 7 beats/min in nonpregnant animals. Pressor responses to angiotensin II, vasopressin, and norepinephrine were attenuated in gravid animals. Infusion of N omega-nitro-L-arginine significantly and in a dose-dependent manner increased mean arterial pressure and reduced heart rate. These effects could be completely reversed by L-arginine administration. Changes in mean arterial pressure were higher during pregnancy as compared with postpartum values. N omega-nitro-L-arginine infusion potentiated pressor responses to all three vasopressors, resulting in dose-response curves that were significantly shifted to the left, making them virtually identical in pregnant and postpartum rats. Our data support the emerging view that nitric oxide plays a key role in the regulation of blood pressure during pregnancy.