The acute renal effects of angiotensin II receptor blockers.
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Angiotensin Receptor Antagonists↗
Biomedical subjects
R Veelken
Publications and source records attributed to R Veelken.
Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage.
Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured in conscious rats during either hemorrhage or cardiopulmonary chemoreceptor stimulation with phenylbiguanide (PBG) after intracerebroventricular injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (40 micrograms). Progressive hemorrhage caused an initial rise (109 +/- 33%) followed by a fall in RSNA (-60 +/- 7%) and a fall in HR (-126 +/- 7 beats/min). Methysergide delayed the hypotension and prevented both the sympathoinhibitory and bradycardic responses to hemorrhage. Systemic 5-HT3-receptor blockade did not influence responses to hemorrhage. The PBG infusion caused transient depressor (-25 +/- 6 mmHg), bradycardic (-176 +/- 40 beats/min), and renal sympathostimulatory (182 +/- 47% baseline) responses that were not affected by central methysergide (-20 +/- 6 mmHg, -162 +/- 18 beats/min, 227 +/- 46% baseline). These data indicate that a central serotonergic receptor-mediated component contributes to the sympathoinhibitory and bradycardic responses to hypotensive hemorrhage in conscious rats. Furthermore, the same central 5-HT-receptor populations involved in reflex responses to hypotensive hemorrhage probably do not mediate the sympathoinhibitory response to cardiopulmonary chemosensitive 5-HT3 receptors.
Animals↗
Neural control of kidney function.
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Animals↗
Angiotensinases restrict locally generated angiotensin II to the blood vessel wall.
We tested the hypothesis that angiotensinases limit the spillover of locally formed angiotensin II into the circulation. The release of angiotensin peptides from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. The spontaneous release of angiotensins was increased by the angiotensinase inhibitors phenanthroline (850+/-195 versus 95+/-33 fmol of angiotensin I per 30 minutes in controls, P<.05, n=5 each) and amastatin (P<.05, n=5 each). Infusion of renin induced sustained local angiotensin I formation, which was also increased by phenanthroline. Stimulation of local angiotensin formation by renin infusion was compared with infusion of exogenous angiotensin II. Renin caused similar increases of perfusion pressure (11.1+/-2.2 versus 7.6+/-1.9 mm Hg after angiotensin II, P>.05) despite lower angiotensin II levels in the venous effluent than during infusion of exogenous angiotensin II (65+/-2 versus 482+/-33 fmol/mL, P<.05, n=7 each). Thus, renin must have caused higher angiotensin II tissue levels than indicated by the measurements in the venous effluent. The pressor response to renin was abolished by the type 1 angiotensin II receptor antagonist losartan. We conclude that the major part of locally generated angiotensins is not released into the circulation but degraded by angiotensinases within the tissue compartment.
Angiotensin I↗
Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension.
The relationship between sympathetic nerve activity and BP in the early stages of essential hypertension remains unclear. To investigate this relationship further, this study measured resting muscle sympathetic nerve activity (MSNA: representing peripheral vasoconstrictor activity), plasma catecholamines, BP, central venous pressure, and heart rate in 20 young (24 +/- 2 SD yr), lean (body mass index, 24.2 +/- 3.0 kg/m2), male subjects with borderline hypertension (BHT) and in 21 male normotensive (NT) control subjects matched for age and body mass index. A cold pressor test was also performed to evaluate sympathetic reflex responsiveness. Resting mean BP and heart rate were significantly higher in the BHT subjects compared with NT subjects (113 +/- 9 versus 89 +/- 9 mmHg; 74 +/- 8 versus 62 +/- 8 bpm; P < 0.0001 each) with no difference in central venous pressure. Resting MSNA levels tended to be lower in the BHT versus the NT group (12 +/- 6 versus 14 +/- 9 bursts/min, P = NS; 16 +/- 8 versus 22 +/- 13 bursts/100 heartbeats, P = 0.05) and did not correlate with either BP or body mass index. Significant positive correlations were found between resting MSNA and plasma norepinephrine levels in both groups (P < 0.05). Hemodynamic and sympathetic nerve responses to the cold pressor test were similar between the BHT and NT subjects. It is concluded that resting MSNA and plasma norepinephrine levels are correlated in young lean NT and BHT men; however, neither of these variables is correlated with BP. Because MSNA was similar in the two groups, the concept that augmented resting MSNA is important in the early developmental phase of essential hypertension must be reevaluated.
Adult↗
Is endothelial function of the radial artery altered in human essential hypertension?
There is controversy over whether endothelial function is impaired in human essential hypertension. All studies to date have used measurements of forearm blood flow by plethysmography to assess endothelium-dependent vasodilation and endothelial function. In contrast to these studies, which have focused on resistance vessels, we have determined what effects the endothelium has on underlying smooth muscle cells in conduit arteries by measuring arterial compliance of the radial arteries (change in diameter of radial artery over pressure for each arterial pulse). In 13 normotensive healthy subjects and 11 young patients with essential hypertension, arterial compliance of the radial artery was assessed directly with a new high-precision ultrasonic device (NIUS 02) after infusion of acetylcholine (endothelium-dependent response) or sodium nitroprusside (endothelium-independent response). Arterial compliance of the radial artery was similar at baseline and with increasing doses of acetylcholine and sodium nitroprusside in normotensive and in hypertensive subjects. The increase in arterial compliance from baseline at each individual concentration of acetylcholine and sodium nitroprusside was the same in both normotensive and hypertensive subjects. However, after a single oral dose of a combination of the angiotensin converting enzyme inhibitor spirapril and the calcium entry blocker isradipine, the increase in arterial compliance in response to the maximum dose of intraarterial acetylcholine was enhanced in normotensives (0.38 +/- 1.23 to 0.76 +/- 1.01 mm2/mm Hg x 10(-3), P < .05), but not in hypertensives (+0.41 +/- 1.26 to 0.36 +/- 1.31 mm2/mm Hg x 10(-3), not significant), and differed significantly between normotensive and hypertensive subjects (P < .05). Thus, pharmacologic stimulation disclosed a blunted response of endothelium-dependent action in the arterial compliance of the conduit arteries in hypertensive subjects. This suggests an impaired endothelial function reserve in persons with essential hypertension.
Acetylcholine↗
Is endogenous erythropoietin a pathogenetic factor in the development of essential hypertension?
BACKGROUND: Recent experimental studies have found that erythropoietin elicits vasoconstriction and proliferation of endothelial cells. We conducted the following study to assess the possible interactions between endogenous erythropoietin, systemic and renal haemodynamics at different stages of essential hypertension. METHODS: We examined 47 patients with borderline essential hypertension (age 26 +/- 3 years) and 49 patients with established essential hypertension WHO stage I-II (age 52 +/- 10 years), and compared them to 42 normotensive individuals (age 26 +/- 3 years). The concentration of erythropoietin (radioimmunoassay), 24-h ambulatory blood pressure (Spacelab 90207), systemic haemodynamics (Doppler sonography) and renal haemodynamics (para-aminohippuric acid and inulin clearance) were determined. RESULTS: Erythropoietin was within normal range and similar among the three groups. In patients with established essential hypertension, a close correlation was found between erythropoietin and systolic (r = 0.45, P < 0.002) and diastolic (r = 0.51, P < 0.001) ambulatory blood pressure. In contrast, ambulatory blood pressure was not correlated with erythropoietin in subjects with borderline hypertension. Total peripheral resistance (r = 0.41, P < 0.02) was linked to erythropoietin in established but not in borderline hypertension. However, erythropoietin was inversely correlated with renal plasma flow in both established and borderline hypertension (r = -0.33, P < 0.05, and r = -0.34, P < 0.05 respectively). In normotensive subjects, in contrast, erythropoietin was not correlated with any of the determined variables. In neither group erythropoietin was linked to the haematocrit or hemoglobin concentration. CONCLUSION: The correlation between erythropoietin and renal vascular changes which is already present in borderline hypertension and is confirmed in established hypertension indicates an involvement of erythropoietin in the development of essential hypertension. The presence of normal concentrations of endogenous erythropoietin in all groups suggests a dysregulation of erythropoietin in patients with essential hypertension as the pathophysiological link between erythropoietin and vascular changes.
Adult↗
Pulmonary serotonin 5-HT3-sensitive afferent fibers modulate renal sympathetic nerve activity in rats.
Cardiopulmonary reflexes with vagal afferents may control volume homeostasis by influencing renal nerve activity. Such reflexes can be stimulated mechanically and chemically, e.g., by serotonin 5-HT). We have demonstrated that stimulation of epicardial 5-HT3 receptors inhibits renal sympathetic nerve activity (RSNA) by a cardiorenal reflex. We now tested the hypothesis that pulmonary 5-HT3-sensitive vagal afferent fibers participate in the control of renal nerve activity. Two sets of experiments were performed. First, the responses of multifiber RSNA, heart rate (HR), and blood pressure (BP) to the 5-HT3-receptor agonist phenylbiguanide (PBG; 10 microg iv) were recorded in the presence of intact pulmonary afferents. Abdominal afferents were removed by subdiaphragmatic vagotomy. Cardiac afferents were blocked by intrapericardial injection of 10% procaine. Second, the responses of 25 single vagal pulmonary afferent C fibers to PBG were assessed. PBG decreased BP, HR, and RSNA (-90 +/- 8%). When cardiac afferents were blocked by procaine, BP and HR failed to decrease in response to PBG; however, the RSNA decrease was still -48 +/- 8%. Single fibers generally responded to PBG by a slight increase in firing rate. A distinct subset of fibers (5 of 25) showed an activity increase of >15 Hz that preceded changes in BP and HR. The decreased RSNA in the absence of cardiac and abdominal vagal afferents and the strong response of 20% of pulmonary single fibers to intravenous PBG suggest that pulmonary fibers play a role in a 5-HT3 serotenergic reflex. Thus pulmonary serotonin could influence the neural control of renal function.
Afferent Pathways↗
Glomerular hyperfiltration during sympathetic nervous system activation in early essential hypertension.
Glomerular hyperfiltration may be important for the development of essential hypertension. Both the renin-angiotensin system and the sympathetic nervous system influence renal hemodynamic regulation. To test the hypothesis that glomerular hyperfiltration can be unmasked by sympathetic nervous system activation, renal hemodynamics and humoral components of the renin-angiotensin system were examined at rest and during mental stress in 45 young normotensive healthy subjects and 37 young people with mild essential hypertension. GFR and renal plasma flow (RPF) were determined with inulin and para-aminohippuric acid clearance at rest and during stress. At rest, RPF, GFR, filtration fraction, plasma renin activity, angiotensin (Ang) II concentrations, and serum aldosterone values were similar in normotensive and hypertensive subjects. After stress, blood pressure increased (P < 0.01), but this was nearly identical in normotensive and hypertensive subjects (7.05 +/- 6.9 versus 7.03 +/- 4.6 mmHg, NS). The decrease in RPF (-27 +/- 54 versus -22 +/- 25 ml/min per 1.73 m2, NS) was also similar in the two groups. In contrast, the increase in GFR (+ 10.5 +/- 7.2 versus 6.08 +/- 5.7 ml/min per 1.73 m2, P < 0.001) and filtration fraction (+2.48 +/- 1.38 versus 1.82 +/- 1.49%, P < 0.05) was more marked in hypertensive than in normotensive subjects. The concomitant increase in Ang II concentrations was greater in hypertensive than in normotensive subjects (+4.6 +/- 1.0 versus -1.0 +/- 0.45 pg/ml, P < 0.001). The increase in GFR during mental stress was correlated with the increment in Ang II concentrations (r = 0.39, P < 0.001). Compared with the placebo control phase, blockade of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor attenuated the increase in GFR during stress in hypertensive (8.04 +/- 5.01 versus 10.1 +/- 5.7 ml/min per 1.73 m2, P < 0.05), but not in normotensive, subjects. Even in early essential hypertension, glomerular hyperfiltration is evident during sympathetic nervous system activation, which is mediated by postglomerular vasoconstriction. This early stress-induced glomerular hyperfiltration may contribute to, or trigger, the development of essential hypertension.
Adult↗
Overview of alpha 1-adrenoceptor antagonism and recent advances in hypertensive therapy.
alpha 1-Receptor antagonists are potent blood pressure lowering drugs, although the use of alpha 1-receptor antagonists by physicians in the treatment of hypertension has been somewhat reserved. The major concern are symptoms of orthostatic dysregulation and syncopes. However, reports on a long-acting second generation of alpha 1-adrenoceptor antagonists demonstrate that orthostatic dysregulation is not more frequent in patients treated with these compounds as compared to other antihypertensive drugs. Since blood pressure readings at patients' work sites are of greater prognostic value for the fatal events of cardiovascular disease, the impact of any antihypertensive agent on cardiovascular reactivity during stress becomes most important. Long-acting alpha-adrenoceptor antagonists control blood pressure during stressful events, ie, stimulation of the sympathetic nervous system without altering the physiologic hemodynamic profile. Sustained elevated blood pressure imposes a burden on the cardiovascular system, in particular on arteries, arterial resistance vessels, the cerebrovascular circulation, the kidneys, and the heart. Since the extent of target organ damage is responsible for the impaired prognosis of the hypertensive patient, regression of early hypertensive organ alterations is a most desirable therapeutic goal. In a series of clinical trials we found that alpha 1-receptor antagonists reduced left ventricular hypertrophy (an independent risk factor for cardiovascular mortality and morbidity), lowered total peripheral resistance (related to vascular resistance vessels), improved glomerular filtration rate, and had no effect or improved lipid metabolism, glucose tolerance, and insulin resistance. Hence, alpha 1-adrenoceptor antagonists emerged as attractive agents for antihypertensive therapy.
Adrenergic alpha-Antagonists↗
Subthreshold stimulation of a serotonin 5-HT3 reflex attenuates cardiovascular reflexes.
Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.
Animals↗
Epicardial bradykinin B2 receptors elicit a sympathoexcitatory reflex in rats.
Bradykinin may be generated in the heart during ischemia and is involved in nociception. We tested the hypothesis that bradykinin elicits a sympathoexcitatory reflex in rats by stimulating cardiac afferent nerve fibers. Rats were implanted with femoral catheters for measurement of blood pressure and heart rate, a bipolar electrode for measurement of renal sympathetic nerve activity, and a pericardial catheter for intrapericardial injection of substances. Rats were slightly anesthetized with hexobarbital so pain reactions were prevented. Graded doses of bradykinin (2.5, 12, 25 micrograms) were injected intravenously or intrapericardially into control rats, intrapericardially after vagotomy, intrapericardially after intrapericardial pretreatment with the bradykinin B2 receptor antagonist Hoe 140, and intrapericardially after cardiac autonomic blockade (intrapericardial pretreatment with 10% procaine). For comparison, the serotonin 5-HT3 agonist phenylbiguanide, a substance known to elicit sympathoinhibitory reflexes by cardiac vagal afferents, and adenosine, putatively inducing sympathoexcitatory responses via the heart, were applied intrapericardially. Bradykinin increased blood pressure when administered intrapericardially but decreased blood pressure when injected intravenously; both intrapericardial and intravenous bradykinin increased renal sympathetic nerve activity. Intrapericardial adenosine had no effect on circulatory control. Intrapericardial pretreatment with the B2 receptor antagonist Hoe 140 completely inhibited the increases of blood pressure and renal sympathetic nerve activity in response to intrapericardial bradykinin but did not affect the responses to intrapericardial phenylbiguanide. Bilateral cervical vagotomy abolished the decreases of blood pressure, heart rate, and renal sympathetic nerve activity after intrapericardial phenylbiguanide but did not influence the responses to intrapericardial bradykinin. Cardiac autonomic blockade with intrapericardial procaine abolished all responses to bradykinin and phenylbiguanide. We conclude that cardiac bradykinin elicits a sympathoexcitatory reflex by epicardial B2 receptors in rats. The afferent portion of the reflex is most likely contained within sympathetic cardiac afferent fibers. Bradykinin may contribute to increased sympathetic nerve activity in pathophysiological situations of coronary artery disease and cardiac ischemia.
Adenosine↗
Nerve-mediated antidiuresis and antinatriuresis after air-jet stress is modulated by angiotensin II.
A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98 +/- 4% (n = 6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31 +/- 3 to 8 +/- 4 microL/min per gram kidney weight, P < .05, n = 12) and sodium excretion (from 4.3 +/- 0.9 to 1.2 +/- 0.3 mumol/min per gram kidney weight, P < .05, n = 12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 micrograms ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve-mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats.
Angiotensin II↗
Predictors for hypertensive nephropathy: results of a 6-year follow-up study in essential hypertension.
OBJECTIVE AND DESIGN: To identify predictors for the development of early hypertensive nephropathy, 88 previously untreated patients with mild-to-moderate essential hypertension (World Health Organization stage I or II) were re-examined after 6 years of follow-up. According to previous results, protein excretion, urinary excretion of N-acetyl-beta-glucosaminidase (NAG), serum NAG concentration and glomerular filtration rate (creatinine clearance) may predict the change in renal function. RESULTS: Serum creatinine level increased significantly, but none of the patients developed serum creatinine of > 1.3 mg/dl. An elevated protein excretion between 200 and 500 mg/day at baseline (microproteinuria), urinary NAG excretion, serum NAG concentration and blood pressure control during treatment were not related to serum creatinine level at follow-up or change in serum creatinine level throughout the 6 years of follow-up. In contrast, a high creatinine clearance at baseline was related to a marked rise in serum creatinine level after 6 years. The patients with a clear-cut increase in serum creatinine level of > 0.2 mg/dl (n = 23) were characterized by a significantly higher pretreatment blood pressure at the worksite and a significantly greater initial creatinine clearance than the patients with no significant change in serum creatinine level. In the two groups age, blood pressure level during therapy, and the intensity and duration of blood pressure control were not different. CONCLUSION: In patients with uncomplicated essential hypertension, microproteinuria, NAG parameters and treatment blood pressure level did not predict the change in serum creatinine level in the first 6 years of follow-up. A high creatinine clearance (suggesting glomerular hyperfiltration) emerged as a clinical diagnostic marker of early hypertensive nephropathy.
Adult↗
Vascular angiotensin and the sympathetic nervous system: do they interact?
We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.
Adrenergic beta-Agonists↗
Vascular renin in the guinea pig. Suppression by the renin inhibitor remikiren.
Angiotensin I and II are generated by the vascular wall. Whether this generation depends on renin or on other enzymes is debated. We tested the hypothesis that remikiren, a highly specific inhibitor of human and guinea pig renin, may inhibit the vascular renin-angiotensin system. Isolated hindquarters from guinea pigs were perfused with an artificial medium, and angiotensin I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Guinea pig hindquarters released angiotensin I (23.8 +/- 5.6 fmol/30 min; n = 13) and angiotensin II (95.2 +/- 19 fmol/30 min; n = 13) spontaneously. Inhibition of the angiotensin I-converting enzyme by captopril (10 nmol/mL) suppressed angiotensin II by 85% and increased angiotensin I by 352% (n = 5, P < .05). Infusion of remikiren (1.6 nmol/mL) in addition to captopril decreased angiotensin I release by 68% (P < .05 versus captopril alone, n = 5 each). We conclude that renin generates angiotensin I in an isolated guinea pig resistance vessel bed. Our study demonstrates that renin rather than nonrenin enzymes is responsible for the major part of vascular angiotensin formation.
Angiotensin I↗
Sympathetic baroreceptor responses after chronic NG-nitro-L-arginine methyl ester treatment in conscious rats.
Blood pressure elevations after nitric oxide inhibition may result in part from increased sympathetic tone. In this study arterial baroreceptor reflex control of heart rate, renal sympathetic nerve activity (RSNA), and adrenal sympathetic nerve activity (ASNA) were compared in rats given normal tap water or a 3.7 nmol/L (10 mg%) solution of NG-nitro-L-arginine methyl ester (L-NAME) for 1 or 5 weeks. L-NAME raised blood pressure after 5 weeks of treatment (153 +/- 3 versus 130 +/- 3 and 124 +/- 2 mm Hg, 5 weeks versus 1 week and control). The sensitivity of arterial baroreceptor reflex control of RSNA was reduced after both 1 and 5 weeks of treatment (-5.05 +/- 0.63% and -4.46 +/- 0.2% versus -6.43 +/- 0.39% baseline activity per millimeters of mercury). Set point gain of ASNA was attenuated after 5 weeks of treatment compared with controls (-1.7 +/- 3% versus -3.3 +/- 3% baseline activity per millimeters of mercury). Maximal inhibition of ASNA was attenuated in groups treated 1 and 5 weeks (60 +/- 3% and 66 +/- 3% versus 34 +/- 4% baseline activity). The maximal increase in both RSNA and ASNA was elevated in rats treated 5 weeks (RSNA: control, 263 +/- 19%; 1 week, 224 +/- 17%; 5 weeks, 324 +/- 20%; ASNA: control, 272 +/- 29%; 1 week, 252 +/- 31%; 5 weeks, 361 +/- 28% baseline activity). The data indicate that chronic L-NAME treatment alters arterial baroreceptor reflexes in part before the onset of hypertension.
Adrenal Glands↗
Impaired cardiovascular reflexes precede deoxycorticosterone acetate-salt hypertension.
We hypothesized that impaired cardiopulmonary reflexes but not altered baroreceptor reflexes precede deoxycorticosterone acetate (DOCA)-salt hypertension. Uninephrectomized rats were given either DOCA and 0.9% NaCl as drinking water, 0.9% NaCl alone, or tap water. We measured mean blood pressure, heart rate, and renal sympathetic nerve activity. After 8 days, mean blood pressure was not different in DOCA-salt and control rats. Volume-sensitive cardiopulmonary reflexes were tested by intravenous volume loading with saline (10% body weight in 15 minutes), which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. This response was blunted in DOCA-salt rats. Chemosensitive cardiopulmonary reflexes were tested by 15-minute infusions of the serotonin 5-HT3 agonist phenylbiguanide, which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. Sustained decreases in renal sympathetic nerve activity occurred during phenylbiguanide infusion in controls but were blunted over time in DOCA-salt rats. The arterial baroreflex responses to graded infusions of methoxamine and nitroprusside were analyzed by sigmoidal curve fitting. There were no differences in gain of renal sympathetic nerve activity or heart rate between the groups. Thus, DOCA-salt rats exhibit impaired cardiopulmonary reflexes before the onset of hypertension; the volume-sensitive reflexes are more severely affected than chemosensitive reflexes. The arterial baroreceptor reflex is unaltered. The decreased sensitivity of cardiopulmonary reflexes may contribute to DOCA-salt hypertension.
Analysis of Variance↗