Kazuhiro Kumagai

Role of nitric oxide in regulation of baroreceptor reflex

The possible role of nitric oxide (NO) on modulating sympathetic nerve activity through its action on baroreceptor reflex arc was investigated. L-Arginine, a precursor of NO, and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, were separately infused intravenously in increasing doses in 126 pentobarbital-anesthetized rabbits. Mean arterial pressure (MAP), heart rate (HR), aortic nerve activity (ANA), cervical (CSNA) and renal sympathetic nerve activities (RSNA) were recorded. L-Arginine infusion decreased MAP (P < 0.05), ANA (P < 0.05), CSNA (P < 0.05) and RSNA (P < 0.05) without changes in HR. Infusion of D-arginine, an enantiomer of L-arginine, and simultaneous infusion of L-arginine and L-NMMA, did not elicit such changes. L-NMMA infusion increased MAP (P < 0.05) and ANA (P < 0.05) and decreased HR (P < 0.05), while it tended to increase CSNA and RSNA without significance. Infusion of L-arginine or L-NMMA did not alter the slope of ANA, CSNA, RSNA, or HR in relation to MAP. These results suggest that NO modulates efferent sympathetic nerve activity, not by altering the afferent or efferent limbs of the baroreceptor reflex arc, but by interacting with the sympathetic pathway in the central nervous system.

Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system.

To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Status of patients who underwent uninephrectomy in adulthood more than 20 years ago

We investigated the status of patients without systemic diseases who had undergone uninephrectomy for unilateral renal diseases in adulthood more than 20 years ago at Tokyo Denryoku Hospital. There were 21 participants (mean age +/- SD, 58.6 +/- 8.0 years) who fulfilled these criteria. The average interval since nephrectomy was 27.9 +/- 6.2 years. The mean current creatinine clearance was 88.5 +/- 21.2 mL/min/1.73 m2, which is 92.9% of that in healthy age- and sex-matched controls with two kidneys. The 24-hour urine protein excretion in these patients was only slightly higher than in the controls (214 +/- 190 mg v 119 +/- 62 mg, P = NS). Age at nephrectomy, length of time with a single kidney, or sex had little effect on the remnant renal functions. There was a positive correlation between current mean arterial pressure and serum creatinine (r = 0.44, P < 0.05). Patients who developed hypertension after uninephrectomy had a family history of hypertension more frequently than those with normotension (86% v 29%, P < 0.05). We conclude that (1) renal function after compensatory hyperfiltration of more than 20 years due to uninephrectomy for unilateral renal diseases in adulthood is well maintained, although hypertension has a considerable effect on the renal functions, and that (2) family history of hypertension plays a key role in determining the incidence of hypertension even in the uninephrectomized patients.

Effects of antihypertensive agents on arterial baroreceptor reflexes in conscious rats.

The effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor reflex control of renal sympathetic nerve activity and heart rate were investigated in 45 conscious spontaneously hypertensive rats and 37 age-matched Wistar-Kyoto rats. Antihypertensive agents were administered for 2 weeks beginning at 8 weeks of age to treat and prevent the development of hypertension. Blood pressure was reduced to a similar level (-13 +/- 3 mm Hg, p < 0.05) by each antihypertensive agent. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded in the conscious state during phenylephrine and nitroglycerin ramp infusion. The gain in the baroreceptor reflex was determined from the maximum slope of logistic function curves. Untreated spontaneously hypertensive rats exhibited decreased sensitivity of reflex control of renal sympathetic nerve activity and heart rate (-1.78 +/- 0.07% of control/mm Hg and -2.16 +/- 0.05 beats per minute/mm Hg, respectively) compared with untreated Wistar-Kyoto rats (-3.62 +/- 0.18% of control/mm Hg, p < 0.01, and -3.46 +/- 0.11 beats per minute/mm Hg, p < 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Basal sympathetic nerve activity is enhanced with augmentation of baroreceptor reflex in Wistar fatty rats: a model of obesity-induced NIDDM.

AIM Wistar fatty rats (WFR) develop mild hypertension associated with obesity, hyperglycaemia and hyperinsulinaemia, and are thus assumed to be a good model of insulin resistance-related hypertension. We determined whether the activity of the sympathetic nervous system and its baroreflex-mediated regulation are involved in the development of hypertension in this strain. METHODS Renal sympathetic nerve activity (RSNA) was recorded in pre-hypertensive WFR (n = 8, age 12 weeks) and Wistar lean rats (WLR) (n = 8) during changes in arterial pressure by phenylephrine and nitroprusside infusion in the conscious state. Baroreflex control of RSNA and heart rate were examined by logistic function analysis. RESULTS The mean arterial pressure (MAP) of WFR was similar to that of WLR (108 +/- 4 versus 101 +/- 2 mmHg, not significant). Basal RSNA was elevated in WFR compared with WLR (86 +/- 2 versus 51 +/- 2% maximum, P< 0.01). Baroreflex control of RSNA was shifted to higher pressure levels (mid-range, 119 +/- 4 versus 99 +/- 4 mmHg, P < 0.05) in WFR compared with WLR, in spite of similar MAP. However, baroreflex sensitivity concerning RSNA was greater in WFR than WLR (3.07 +/- 0.15 versus 1.63 +/- 0.12% maximum/mmHg, P < 0.01). Baroreflex control of heart rate was also shifted to higher pressure levels (mid-range 129 +/- 4 versus 100 +/- 5 mmHg, P < 0.01) and its sensitivity was increased in WFR compared with WLR (4.62 +/- 0.51 versus 3.16 +/- 0.10 bpm/mmHg, P< 0.05). CONCLUSION These results suggest that baroreflex is not impaired in spite of elevation of blood pressure and that the raised sympathetic nerve activity may contribute to the development of hypertension in WFR.

Comparison of Early and Late Start of Antihypertensive Agents and Baroreceptor Reflexes

Along with arterial blood pressure reduction, maintenance of the integrity of baroreceptor reflex function contributes to preserving end-organ function in the treatment of hypertensive patients. The purpose of this study was to investigate the effects of antihypertensive agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on baroreceptor reflex function by comparing early and late starts of treatment. We administered each agent to spontaneously hypertensive rats (SHR) as early-start groups from 10 to 36 weeks of age and as late-start groups from 28 to 36 weeks of age. We evaluated the gain of the reflex control of renal sympathetic nerve activity and heart rate using ramp infusions of phenylephrine and nitroglycerin in untreated SHR at 10, 28, or 36 weeks of age and in treated SHR at 36 weeks of age. In 28- and 36-week-old untreated SHR, the renal sympathetic nerve activity gain was not altered and the heart rate gain was decreased (from -2.3 +/- 0.3 to -1.3 +/- 0.3 and -1.2 +/- 0.3 beats per minute [bm]/mm Hg, P < .05, respectively) compared with 10-week-old SHR. Early and late start of therapy produced arterial pressure reductions (-18 +/- 4 and -12 +/- 5 mm Hg, P < .05, respectively). In the early-start groups, the renal sympathetic nerve activity gain was improved markedly in nicardipine- and enalapril-treated SHR (-4.2 +/- 0.2% and -4.9 +/- 0.2% of control/mm Hg, P < .01, respectively), and the heart rate gain was improved markedly in atenolol- and enalapril-treated SHR (-4.1 +/- 0.2 and -4.4 +/- 0.2 bpm/mm Hg, P < .01, respectively). In the late-start groups, the renal sympathetic nerve activity gain was improved moderately in nicardipine- and enalapril-treated SHR (-3.8 +/- 0.2% and -2.9 +/- 0.2% of control/mm Hg, P < .05, respectively). The heart rate gain was improved slightly only in nicardipine-treated SHR (-1.9 +/- 0.2 bpm/mm Hg, P < .05). These results demonstrate that an early start of antihypertensive treatment improves baroreceptor reflex function markedly compared with a late start of treatment. This supports the hypothesis that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension and indicates that the early start of antihypertensive treatment would be required in clinical practice.

Role of vasopressin in salt-induced hypertension in baroreceptor-denervated uninephrectomized rabbits.

To elucidate the contributions of renal, humoral, and arterial baroreceptor reflex components to salt-induced hypertension, we administered 10% NaCl intravenously for 10 days to sinoaorticdenervated rabbits with unilateral nephrectomy (n=7), sinoaortic-denervated rabbits with intact kidneys (n=7), and sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy (n=7). Serial changes in mean arterial pressure (MAP), heart rate, and blood pressure variability were recorded. In sinoaortic-denervated rabbits with unilateral nephrectomy, MAP increased significantly from 109±2 to 124±3 mm Hg (day 4) and remained elevated for the rest of the experiment This elevation of MAP was accompanied by a reduction in the standard deviation of MAP, with significant elevations in plasma vasopressin, norepinephrine, and atrial natriuretic peptide concentrations and in sodium retention. In the other groups, there were no significant changes in these vasoactive hormones. In the sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy, sodium retention was similar to that of sinoaorticdenervated rabbits with unilateral nephrectomy. Continuous infusion (1 μg/kg/hr) of a V1 antagonist prevented the elevation of blood pressure and plasma norepinephrine, the accumulation of sodium, and the reduction of blood pressure lability, whereas a bolus injection (10μg/kg) on day 4 reduced blood pressure from 128±3 to 115±2 mm Hg (p<0.005). These results imply that vasopressin plays a crucial role in the expression of salt-induced hypertension in rabbits with compromised baroreceptor and renal function.

Differential Modulation of Baroreceptor Sensitivity by Long-term Antihypertensive Treatment

We investigated the effects of long-term oral treatment with four different classes of antihypertensive drugs (a thiazide diuretic [trichlormethiazide, 10 mg/kg per day]; a beta-blocker [atenolol, 90 mg/kg per day]; a calcium channel antagonist [nicardipine, 150 mg/kg per day]; and an angiotensin-converting enzyme inhibitor [enalapril maleate, 10 mg/kg per day]) on aortic baroreceptor activity in spontaneously hypertensive rats with chronic hypertension (36 weeks of age). Treatment with each of the four drugs, given from 10 to 36 weeks of age, similarly decreased arterial pressure (171 +/- 2 to 144 +/- 1 mm Hg, P < .01) and similarly decreased the threshold pressure for baroreceptors (116 +/- 3 to 103 +/- 1 mm Hg, P < .05). The four antihypertensive drugs also potentiated the maximal gain of the pressure-activity relation in these rats (untreated, 1.08 +/- 0.05% maximum/mm Hg); however, nicardipine and enalapril (1.77 +/- 0.04% and 1.70 +/- 0.06% maximum/mm Hg, respectively) augmented the maximal gain to a greater extent (P < .05 to .01) than did trichlormethiazide or atenolol (1.49 +/- 0.05% and 1.42 +/- 0.02% maximum/mm Hg, respectively). When the initiation of treatment was delayed to 28 weeks of age, no differences were found in the effects on either threshold pressure (104 +/- 1 mm Hg) or maximal gain (1.36 +/- 0.03% maximum/mm Hg) for all four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of antihypertensive agents on baroreceptor function in early hypertensive rats.

To investigate the effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor function at the early phase of hypertension, we administered the agents to spontaneously hypertensive rats and Wistar-Kyoto rats from 8 to 10 weeks of age and examined the aortic nerve activity function. In untreated spontaneously hypertensive rats, the relation between the arterial pressure and aortic nerve activity was shifted to the right, that is, to a higher pressure level (threshold pressure, 90 +/- 3 versus 76 +/- 1 mm Hg, P < .05), and the maximum gain which was obtained by logistic function analysis was depressed (1.55 +/- 0.08% versus 2.18 +/- 0.13% maximum/mm Hg, P < .01) as compared with untreated Wistar-Kyoto rats. An equivalent decrease in arterial pressure with each of the four agents (-20 +/- 1 mm Hg, P < .01) produced a leftward shift of the arterial pressure-aortic nerve activity relation to a similar extent (threshold pressure, 77 +/- 1 mm Hg, P < .05) in spontaneously hypertensive rats. In addition, treatment with the four agents equally augmented the maximum gain in spontaneously hypertensive rats (2.13 +/- 0.09% maximum/mm Hg, P < .05). The antihypertensive agents affected neither the blood pressure nor the aortic nerve activity in Wistar-Kyoto rats. These findings suggest that antihypertensive treatment with the four classes of agents equally enhances the arterial baroreceptor function through blood pressure reduction but not through specific depressor mechanisms at the early stage of hypertension.

Different responses of renal blood flow and sympathetic nerve activity to captopril and nicardipine in conscious renal hypertensive rabbits

To elucidate the roles of endogenous angiotensin II (AII) and renal sympathetic nerve activity (RSNA) in modulation of renal blood flow (RBF), we recorded RBF and RSNA in conscious two-kidney, one-clip (2K1C) hypertensive rabbits with blood pressure (BP) reduced to a similar extent by captopril (5 mg/kg) and nicar-dipine (4.3 μg/kg/min). We measured plasma concentrations of AII, arginine vasopressin (AVP), and norepi-nephrine (NE). Despite comparable depressor effects, changes in RBF showed different profiles with the two drugs in renal hypertensive rabbits. After captopril injection, RBF was consistently increased to 143 ± 7%. In contrast, with nicardipine infusion, RBF was initially increased to 114 ± 5% and then significantly decreased to 86 ± 4%. The increase in RSNA was greater with captopril than with nicardipine. Plasma concentration of AII was decreased with captopril but significantly increased with nicardipine. In sham-clipped normotensive rabbits in which plasma AII was not increased, RBF was not reduced with nicardipine. Thus, vasoconstrictor actions of RSNA and increased AII may have overcome the va-sodilatory effect of nicardipine in conscious renal hypertensive rabbits. Because the increase in RSNA was smaller with nicardipine, we speculate that the vasocon-striction induced by AII, as well as background BP level, played a substantial role in determining RBF.