- Email: [email protected]
Role of angiotensin II in salt-induced increase in blood pressure and renal injury during chronic nitric oxide inhibition
WS4-J-3-03 THE ROLESOF ENDOGENOUSVASODILATORSIN THE CONTROLOF GLOMERULARHEMODYNAMICS. S. Arima 1 , S. Ito 2, K. Omata3, K. Abe3 1) Dept. of Clinical Biology & Hormonal Regulation, TohokuUniv. School of Medicine, Sendal, Japan 2) Hypertension Research Div., Henry Ford Hosp., Detroit, MI, USA 3) 2nd Dept. of Internal Medicine, Tohoku Univ. School of Medicine, Sendai, Japan Preglomerular afferent (Af-) and postglomerularefferent arterioles (Ef-Arts) are crucial vascular segments in the control of glomerular hemodynamics. The balance of vascular tone between Af- and Ef-Arts critically affects the glomerular capillary pressure and thereby the glomerular filtration rate. However, their vascular reactivity is incompletely understood. In this study, we examined 1) their responses to angiotensin II (Ang II) and norepinephrine (NE), and 2) the possible modulatory roles of nitric oxide (NO) and prostaglandins (PGs) in these responses. Rabbit Af- or Ef-Arts were microdissected and perfused at constant pressure. El-Arts were perfused in either the orthograde direction from the distal end of Af-Arts through the glomerulus (orthograde perfusion; OP) or the retrograde direction from its distal end to eliminate the influence of the glomerulus (retrograde perfusion; RP). Thus, by comparing the vascular reactivity of El-Arts between OP and RP, we could estimate the effects of vasoactiva substances produced by the glomerulus on the vascular reactivity of the Ef-Art. Although Ang II and NE constricted beth arterioles in a dose-dependent manner, sensitivity to Ang II but not to NE was higher in Ef-Arts than Af-Arts. Ang II began to cause significant (P<0.01) constriction from 10-9M (11¢3%, n=l f ) in Af-Arts and from 10-11M in Ef-Arts (OP; 11¢4%, n=9. RP; 10¢2%, n=5), whereas NE began to cause significant constriction from 10-7M in both arterioles. Moreover, both Ang II and NE at higher concentrations produced much stronger (P<0.01) constriction in Ef-Arts with RP than OP; Ang II at 10-8 M or NE at 10-6 M decreasedthe diameter by 35+4% or 25+4% in OP and 74:1:4"/.or 62+7% in RP. These results suggest following two possibilities; 1) vasoconstrictoreffect of Ang II may be modulated in the Af-Art, and 2) vasoactive substance(s) released by the glomerulus could reach the downstream Ef-Art and modulate its vascular reactivity. NO synthesis inhibition with nitro-L-arginine (L-NAME; 10-4M) increased the sensitivity of Af-Art to Ang II without affecting the vascular reactivity of Ef-Arts; in L-NAME-pretreated Af-Arts, Ang II began to cause significant constriction from 10-10 M (14+4%, n=9, P<0.01). Thus, pretreatment with L-NAME significantly decreased the differences in sensitivity to Ang II between Af- and Ef-Arts without affecting different vascular responses of El-Arts between OP and RP, suggesting that NO contributes to the different sensitivity to Ang II between Af- and Ef-Art. Cyclooxygenase inhibitor indomethacin (5x10-5 M) significantly (P<0.01) augmented the Ang It- or NE-induced Ef-Art constriction only in OP; Ang II at 10-8 M or NE at 10-6 M now decreased the diameter by 72+5% (n=8) or 48¢3% (n=7). Thus, pretreatment with indomethacin markedly diminished the differences in responses between OP and RP, suggesting that PGs contribute to the different responses between OP and RP. These results suggest that 1) NO modulates Ang II action only in the Af-Art, contributing to the different sensitivity to Ang II between Af- and Ef-Art, and 2) the glomerulus controls its own capillary pressure by releasing PGs and thereby adjusting the resistance of the downstream Ef-Art. Furthermore, we have recently examined the effects of hyperglycemia,the hallmark of diabetes, on the vascular reactivity of Af-Art and found that increase in extracellular glucose (30 mM) inhibits NO synthesis, resulting in augmentation of Ang It action in the Af-Art. Thus, abnormal glomerular hemodynamicsaccompanies with diabetes may be partly due to the impaired modulatoryrole of NO in the vascular reactivityof Af-Art.
WS4-J-3-04 ROLE OF ANGIOTENSIN II IN SALT-INDUCED INCREASE IN BLOOD PRESSURE AND RENAL INJURY DURING CHRONIC NITRIC OXIDE INHIBITION Y. Konishi, M .Okamura, M. Nishimura, N. Negoro, T .Inoue, Y. Kanayama, and T. Takeda The First DepL Internal Medicine, Osaka City University Medical School, Osaka, Japan Nilric oxide (NO) and angiotensin I/play a role in regulation of vascular tone and sodium handling. It is reported that salt-loading induced increase in arterial pressure during NO inhibition, however, involvement of renin-angiotensin system in the pressor effect of salt-loading is not clear. The objective of this stidy was determine the role of angiotensin 11 in mediating the arterial pressure and renal response to increment of sodium intake during chronic NO inhibition. Studies were conducted in six groups of Wistar rats. Group I , group 11 and group HI were fed by normal sodium diet and group IV, group V and group VI wer fed by high sodium diet. Group 11, 111,V and VI rats were placed on oral L-N~-nitroarginine-methyester (L-NAME) (lg/L drinking water) for 4 weeks. In group HI and VI, the angiotensin II receptor antagonist TCV-116 was administered by gavage at a single daily dose of 2mg/kg. Blood pressure increased at the end of experimental period with L-NAME treatment in both group II and group V. A significant increase in blood pressure was observed in group V compared to group 1I. During inhibition of NO, the pressure-natriuresis relationship is shown to be shifted rightward with the depressed slope. The angiotensin II receptor antagonist TCV-116 attenuated the LNAME induced hypertension in both group HI and group VI. As compared to groups with chronic NO inhibition, the pressure-natriuresis relationship in TCV-116 Ireated group with chronic NO inhibition is shown to be shifted leftward with normalized steep slope. Urinary protein excreation and glomerular sclerotic injury score in chronic salt-loading group is greater than that in normal-salt group during chronic NO inhibition (group V vs. group 11, P<0.05). TCV-116 attenuated proteinuria and glomerular injury during NO inhibition in both normal sodium diet (grouplI vs. grouplII, P<0.05) and high sodium diet (group V vs. groupVI, P<0.05). In this study, acceleration of systemic hypertension and glomerular injury by salt-loading during NO inhibition is observed. NO might participate in the physiological renal adaptation to salt-loading and its inhibition induce salt-sensitive hypertension. Inhibition of NO enhances or uncovers the action of angiotensin 11 on glomerular microcirculation and tubular sodium reabsorption.
276
WS4-J-3-04 ROLE OF ANGIOTENSIN II IN SALT-INDUCED INCREASE IN BLOOD PRESSURE AND RENAL INJURY DURING CHRONIC NITRIC OXIDE INHIBITION Y. Konishi, M .Okamura, M. Nishimura, N. Negoro, T .Inoue, Y. Kanayama, and T. Takeda The First DepL Internal Medicine, Osaka City University Medical School, Osaka, Japan Nilric oxide (NO) and angiotensin I/play a role in regulation of vascular tone and sodium handling. It is reported that salt-loading induced increase in arterial pressure during NO inhibition, however, involvement of renin-angiotensin system in the pressor effect of salt-loading is not clear. The objective of this stidy was determine the role of angiotensin 11 in mediating the arterial pressure and renal response to increment of sodium intake during chronic NO inhibition. Studies were conducted in six groups of Wistar rats. Group I , group 11 and group HI were fed by normal sodium diet and group IV, group V and group VI wer fed by high sodium diet. Group 11, 111,V and VI rats were placed on oral L-N~-nitroarginine-methyester (L-NAME) (lg/L drinking water) for 4 weeks. In group HI and VI, the angiotensin II receptor antagonist TCV-116 was administered by gavage at a single daily dose of 2mg/kg. Blood pressure increased at the end of experimental period with L-NAME treatment in both group II and group V. A significant increase in blood pressure was observed in group V compared to group 1I. During inhibition of NO, the pressure-natriuresis relationship is shown to be shifted rightward with the depressed slope. The angiotensin II receptor antagonist TCV-116 attenuated the LNAME induced hypertension in both group HI and group VI. As compared to groups with chronic NO inhibition, the pressure-natriuresis relationship in TCV-116 Ireated group with chronic NO inhibition is shown to be shifted leftward with normalized steep slope. Urinary protein excreation and glomerular sclerotic injury score in chronic salt-loading group is greater than that in normal-salt group during chronic NO inhibition (group V vs. group 11, P<0.05). TCV-116 attenuated proteinuria and glomerular injury during NO inhibition in both normal sodium diet (grouplI vs. grouplII, P<0.05) and high sodium diet (group V vs. groupVI, P<0.05). In this study, acceleration of systemic hypertension and glomerular injury by salt-loading during NO inhibition is observed. NO might participate in the physiological renal adaptation to salt-loading and its inhibition induce salt-sensitive hypertension. Inhibition of NO enhances or uncovers the action of angiotensin 11 on glomerular microcirculation and tubular sodium reabsorption.
276