Kazutoshi Komatsu

Ventrolateral Medulla AT1 Receptors Support Blood Pressure in Hypertensive Rats

Abstract—Angiotensin within the central nervous system appears to be important for the maintenance of hypertension in spontaneously hypertensive rats. This study addresses the hypothesis that blockade of AT1 receptors in the rostral ventrolateral medulla would decrease blood pressure in spontaneously hypertensive rats and that this tonically active AT1-mediated input to the rostral ventrolateral medulla arises from the hypothalamic paraventricular nucleus. Injection of the nonpeptide AT1 receptor antagonist valsartan bilaterally into the rostral ventrolateral medulla of choralose-anesthetized adult spontaneously hypertensive rats produced a dose-related decrease in mean arterial pressure, with a maximal effect of ≈30 mm Hg. Inhibition of the paraventricular nucleus by local injection of muscimol elicited a similar response, which was inhibited by prior injection of valsartan into the rostral ventrolateral medulla. In contrast, in control Wistar-Kyoto rats, neither valsartan injected into the rostral ventrolateral medulla nor muscimol injected into the paraventricular nucleus had a substantial effect on arterial pressure. These data indicate that in spontaneously hypertensive rats but not in Wistar-Kyoto rats, rostral ventrolateral medulla vasomotor neurons are tonically excited by endogenous stimulation of AT1 receptors, and this input is apparently driven from the hypothalamus. These results suggest that the rostral ventrolateral medulla is one site that the brain renin-angiotensin system acts to maintain elevated blood pressure in spontaneously hypertensive rats.

Glomerular Dynamics and Morphology of Aged Spontaneously Hypertensive Rats: Effects of Angiotensin-Converting Enzyme Inhibition

Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension-converting enzyme inhibitor-treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200 +/- 6 vs 119 +/- 4 mm Hg; P < 0.01), effective renal plasma flow (ERPF) was reduced (1.47 +/- 0.21 vs 3.06 +/- 0.26 ml/min/per g; P > 0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (P < 0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174 +/- 17 vs 80 +/- 9 ml/min; P < 0.01), and single-nephron filtration fraction and afferent arteriolar resistance (RA) were increased (19.4 +/- 1.8 vs 30.0 +/- 2.5% and 1.90 +/- 0.25 vs 9.05 +/- 1.35 U, respectively; both P < 0.01). Despite reduced SNPF, glomerular capillary pressure (PG) increased (49.7 +/- 0.7 vs 53.8 +/- 1.3 mm Hg; P < 0.05), the result of efferent arteriolar constriction (1.15 +/- 0.18 vs 2.84 +/- 0.36 U; P < 0.01). Untreated SHR had higher UPE (13.9 +/- 1.5 vs 42.8 +/- 3.2; mg/100 g per day; P < 0.01) and GIS and AIS scores than WKY (4.3 +/- 1.1 vs 64.3 +/- 8.4 and 16.6 +/- 3.1 vs 96.3 +/- 14.4; both P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical stimulation of the locus coeruleus: inhibitory effects on hemodynamics and renal sympathetic nerve activity

We examined the role of the locus coeruleus (LC) in the regulation of the hemodynamics and sympathetic nerve activity in anesthetized rats. Unilateral microinjection into the LC of the excitatory amino acid, L-glutamate (Glu), elicited dose-dependent decreases in arterial pressure (AP) and heart rate (HR). The bradycardic response was partially attenuated after intravenous injection of atropine sulfate, but the greater part of this response still remained. Interruption of the ascending projections of the LC by midbrain transection did not affect the depressor and bradycardic responses elicited by chemical stimulation. The renal sympathetic nerve activity showed transient but strong inhibition with this stimulation. Cardiac output was measured using an electromagnetic flowmeter implanted in the ascending aorta. The stroke volume and total peripheral resistance (TPR) were calculated. Microinjection of Glu elicited a significant decrease in TPR and slight decreases in cardiac output and stroke volume. Microinjection of the inhibitory amino acid, gamma-aminobutyric acid (GABA), or the alpha 2-adrenergic agonist, clonidine, exerted no effect on AP and HR. The present results therefore suggest that: (1) the LC neurons have an inhibitory influence on the sympathetic nervous system, and stimulation of these neurons can elicit depressor and bradycardic responses; (2) the depressor response was produced predominantly as a result of a decrease in vascular resistance, rather than a decrease in cardiac output; (3) these inhibitory responses may be provided not via the ascending projections of the LC; and (4) the LC neurons do not have a tonic influence on the cardiovascular system.

Complement Activation Accelerates Glomerular Injury in Diabetic Rats

A known inhibitor of the complement cascade (K-76 COONa) was administered to an inbred diabetic rat model to investigate whether the complement system may play a role in the progression of diabetic glomerulosclerosis. Drinking water containing K-76 COONa was available continuously to inbred diabetic rats (Otsuka Long-Evans Tokushima Fatty, OLETF) from the age of 25 to 55 weeks (Group L). Drinking water without K-76 COONa was similarly available to OLETF rats (Group H) and nondiabetic control rats (Long-Evans Tokushima Otsuka, LETO) (Group C). The levels of plasma glucose (mg/dl) at the 55th week were 156 ± 16 in Group C, 252 ± 18 in Group L and 349 ± 93 in Group H. There was no significant difference in the degree of diabetes between Group L and Group H. The levels of urinary protein at 55 weeks of age (mg/day) were 2.1 ± 0.4 in Group C, 11.6 ± 1.5 in Group L and 18.0 ± 2.8 in Group H. The level of urinary protein was significantly decreased by the administration of K-76 COONa. Histological examination of renal specimens from the sacrificed rats at 55 weeks of age revealed diffuse mesangial expansion in almost all glomeruli in Group H, exudative lesions in 30% of glomeruli in Group H, and only mild mesangial expansion was recognized in Group L. Immunofluorescence study revealed brilliant staining of C3 and immunoglobulins (Ig) in Group H; trace staining of Ig and no staining of C3 were recognized in Group L. The incubation study with guinea pig serum and glomeruli from rats revealed that Ig and complement components also bound to injured glomeruli in vitro. These data indicate that the complement cascade is activated by injured glomeruli and this activation exacerbates diabetic glomerulosclerosis.

Acute Effects of Physical Exercise on Prefrontal Cortex Activity in Older Adults: A Functional Near-Infrared Spectroscopy Study

We examined the acute effect of physical exercise on prefrontal cortex activity in older adults using functional near-infrared spectroscopy (NIRS). Fourteen older adults visited our laboratory twice: once for exercise and once for the control condition. On each visit, subjects performed working memory tasks before and after moderate intensity exercise with a cycling ergo-meter. We measured the NIRS response at the prefrontal cortex during the working memory task. We found that physical exercise improved behavioral performance of the working memory task compared with the control condition. Moreover, NIRS analysis showed that physical exercise enhanced the prefrontal cortex activity, especially in the left hemisphere, during the working memory task. These findings suggest that the moderate intensity exercise enhanced the prefrontal cortex activity associated with working memory performance in older adults.

Enhanced serotonin-mediated responses in the nucleus tractus solitarius of spontaneously hypertensive rats.

Previous studies have demonstrated that injection of serotonin into the nucleus tractus solitarius (NTS) elicits hypotension and bradycardia in rats. The present study sought to further characterize this response and to examine the role of serotonergic mechanisms in the NTS in cardiovascular regulation in spontaneously hypertensive (SHR) rats. Injections of picomole amounts of serotonin into the NTS of chloralose-anesthetized normotensive Sprague-Dawley (S-D) or Wistar-Kyoto (WKY) rats produced hypotension and bradycardia that were eliminated by prior injection into the NTS of the selective 5HT(2) antagonist sarpogrelate. Bilateral injection of sarpogrelate did not alter blood pressure or reflex changes in heart rate in response to phenylephrine-induced increases in blood pressure or nitroprusside-induced decreases in blood pressure. In SHR rats, the depressor response produced by injection of serotonin into the NTS was markedly larger than in WKY rats, and was larger than depressor responses previously reported for other excitatory substances injected into the NTS. In SHR rats bilateral injection of sarpogrelate produced an increase in blood pressure, although it did not alter baroreceptor-evoked changes in heart rate. These results provide further support for the hypothesis that stimulation of 5HT(2) receptors in the NTS contributes to cardiovascular regulation independent of the baroreceptor reflex. Furthermore, this serotonergic system is altered in SHR rats, apparently acting tonically to reduce blood pressure.

Hydrochlorothiazide Increases Efferent Glomerular Arteriolar Resistance in Spontaneously Hypertensive Rats

Background: Micropuncture studies were performed to determine the intrarenal hemody namic effects of two conventional antihypertensive agents, hydrochlorothiazide (HCTZ) and hydralazine (HYDR) alone and in combination. Methods and Results: Male spontaneously hypertensive and normotensive Wistar Kyoto rats (19 weeks old) were treated for 3 weeks with vehicle (control), HCTZ (80 mg/kg/d), HYDR (5 mg/kg/d), or combined therapy (HCTZ 30 mg/kg/d and HYDR 2 mg/kg/d). Each treatment significantly reduced arterial pressure while effective renal plasma flow, glomerular filtration rate and single nephron glomerular filtration rate were unaffected by any treatment in either strain. In spontaneously hypertensive rats HCTZ decreased single nephron plasma flow (11 ± 8 to 84 ± 4 nL/min; P < .05) but, despite this reduction, glomerular pressure remained unchanged (51.4 ± 0.7 to 52.1 ± 0.8 mmHg) attributable to increased efferent glomerular resistance (1.58 ± 0.14 to 2.11 ± 0.12 10 U; P < .05). By contrast, HYDR increased single nephron plasma flow (to 147 ± 8 nL/min; P < .01) and decreased efferent glomerular resis tance (to 1.09 ± 0.09 U; P < .05). Combined treatment produced responses similar to HCTZ when used alone, thereby nullifying the beneficial efferent glomerular resistance effects: sin gle nephron plasma flow ± fell (to 89 ± 7 nL/min; P < .05) and efferent glomerular resistance increased (to 2:05 ± 0.17 U; P < .05). In Wistar Kyoto rats, HCTZ and combined treatment had no-effect. HCTZ alone induced glomerular ischemia that was associated with efferent glomerular arteriolar constriction in these spontaneously hypertensive rats. Conclusions: These findings provide a possible explanation for the lack of improved renal target-organ damage in controlled multicenter trials employing thiazide diuretics.

PRESSOR RESPONSES TO SEROTONIN INJECTED INTO THE NUCLEUS TRACTUS SOLITARIUS OF SPRAGUE-DAWLEY RATS AND SPONTANEOUSLY HYPERTENSIVE RATS

Previous studies in rats have shown that injection of nanomoles of serotonin (5-hydroxytryptamine; 5HT) into the nucleus tractus solitarius (NTS) acts on 5HT3 receptors to increase arterial pressure (AP). We investigated the effect of 5HT in Sprague-Dawley (SD) rats and in spontaneously hypertensive rats (SHR). Injection of nanomoles of 5HT into the NTS of chloralose-anesthetized SD rats increased AP. This effect was inhibited by prior injection of 5HT3 receptor antagonist ondansetron. The GABAA receptor antagonist bicuculline did not inhibit the effect of 5HT. Bilateral injection of 5HT or ondansetron did not affect the baroreflex sensitivity. Bilateral injection of ondansetron did not alter AP. The pressor effect of 5HT was exaggerated in SHR. These results suggest that stimulation of 5HT3 receptors in the NTS increases AP independently of activation of GABAA receptors and the baroreflex sensitivity. Furthermore, this serotonergic system is supersensitive in the NTS of SHR.

Enhanced response from the caudal pressor area in spontaneously hypertensive rats.

The caudal pressor area (CPA), located in the caudal extension of the ventrolateral medulla, tonically activates the rostral ventrolateral medulla (RVLM) vasomotor neurons and regulates arterial pressure (AP) in normotensive animals. It is well established that sympathoexcitatory outflow from the RVLM in spontaneously hypertensive rats (SHR) is elevated compared to normotensive animals. Several studies have reported different cardiovascular responses to pharmacological alteration of the RVLM in SHR. Although the CPA may be one of the sources of presympathoexcitatory influence to the RVLM vasomotor drive in normotensive animals, it is unclear whether hypertensive animals such as SHR differ in their response to vasomotor drive evoked from the CPA. In this study, we examined whether sympathoexcitatory influence evoked from the CPA is enhanced in SHR. Local injection of glutamate into the CPA of chloralose-anesthetized male SHR elicited a substantially greater pressor response than in Wistar-Kyoto (WKY) rats, whereas the pressor response evoked by local injection of glutamate into the RVLM was the same in both strains. Furthermore, injection of glycine into the CPA decreased blood pressure to a greater extent in SHR than in WKY rats. These results suggest that the sympathoexcitatory influence of the CPA is enhanced in SHR. Therefore, the enhancement of sympathoexcitatory vasomotor drive evoked from the CPA may, at least in part, support elevated AP and regulate sympathetic tone in this hypertensive model.

Intrarenal Hemodynamics in Low- and High-Output Cardiac Failure in Rats

Cardiac failure is multifactorial in causation, and the underlying physiologic mechanisms are variable, yet their renal effects have been considered more homogeneous. To investigate and compare the intrarenal hemodynamic characteristics in two experimental types (low-and high-output) of cardiac failure, renal micro-puncture studies were performed in rats after myocardial infarction (MI) and arteriovenous fistula, respectively. Myocardial infarction was produced by ligation of the left main coronary artery and arteriovenous fistula by direct puncture of the aorta and inferior vena cava below the renal arteries. Pressures and interrenal and glomerular dynamics were obtained using classic micropuncture techniques. Both forms of cardiac failure were characterized by elevated left ventricular end-diastolic pressure (LVEDP), reduced mean arterial pressure, and increased cardiac mass. Left ventricular end-diastolic pressure was higher in MI rats, and effective renal plasma flow (ERPF) tended to be reduced in both forms of cardiac failure. There were no apparent differences in effective renal plasma flow between two models. In addition, single-nephron plasma flow and single-nephron glomerular filtration rate were reduced, and single-nephron filtration fraction and glomerular capillary pressure (PG) were increased in both models. These changes were associated with higher afferent and efferent arteriolar resistances and lower ultrafiltration coefficients. Despite these similarities, PQ was higher in MI rats, yet LVEDP correlated directly with PG (r = 0.73; P < 0.001) and efferent arteriolar resistances (r = 0.72; P < 0.01). Therefore, although systemic arterial pressure and effective renal plasma flow were similar in both models of cardiac failure, PG was significantly higher in MI rats with higher LVEDP than in arteriovenous fistula rats. Base on these findings, it is suggested that LVEDP may provide the most sensitive cardiac and systemic hemodynamic determinants of altered intrarenal hemodynamics in cardiac failure.