Hemodynamic comparison of diltiazem and TA-3090 in spontaneously hypertensive and normal Wistar-Kyoto rats

Systemic and regional hemodynamic effects of 2 benzothiazepine derivatives, diltiazem and its congener TA-3090, were studied both acutely and chronically in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radiomicrosphere method. Mean arterial pressure was reduced significantly with both immediate and more long-term treatment with both drugs in the SHR. The hypotensive action of TA-3090 was about 3 times as potent as diltiazem. The pressure reduction with both drugs was associated with a decrease in total peripheral resistance. TA-3090 seemed to have lesser effect on heart rate than diltiazem, although its net effect on cardiac output was similar, remaining unchanged in each study group. After intravenous injection, both diltiazem and TA-3090 significantly reduced vascular resistances of the major target organs of hypertension: heart, brain and kidneys in SHR. However, with prolonged treatment, organ vascular resistances seemed to be nonuniformly distributed. Intrarenal hemodynamics revealed significant differences between SHR and WKY rats after intravenous diltiazem and prolonged treatment with TA-3090. Thus, efferent as well as afferent arteriolar resistance decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent resistance and glomerular pressure remained unchanged in WKY rats. In contrast, intravenous TA-3090 evoked no such differences. Thus, diltiazem as well as TA-3090 dilated efferent as well as afferent arterioles in the SHR but not in the WKY rats. This effect was associated with a reduction in glomerular capillary pressure, preventing glomerular hyperfiltration through efferent arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immediate and prolonged hemodynamic effects of TA-3090 on spontaneously hypertensive [SHR] and normal Wistar-Kyoto [WKY] rats

Summary Systemic and regional hemodynamic effects of the new effects of the new calcium antagonist TA-3090, a benzothiazepine derivative that is similar to diltiazem, were studied both acutely (0.3 and 0.6 mg/kg IV) and chronically (30 mg/kg by once-daily gastric gavage for 3 weeks) in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radio-microsphere method. Mean arterial pressure was reduced significantly by both immediate and long-term treatment in both rat strains. Stroke index remained unchanged in each study group, but the heart rate of the SHR and WKY decreased and increased, respectively, with the higher dose in the intravenous aspect of this study. As a result, total peripheral resistance decreased significantly in all groups, normotensive or hypertensive, although this fall was not distributed uniformly throughout the body. Intrarenal hemodynamics revealed significant differences between SHR and WKY by prolonged treatment with TA-3090. Efferent as well as afferent glomerular arteriolar resistances decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent glomerular arteriolar resistance and glomerular pressure remained unchanged in WKY. By contrast, in the acute study, no such differences were obtained. Further, 3 weeks' treatment did not alter cardiac mass in either rat strain. Thus, TA-3090 decreased arterial pressure through a fall in total peripheral resistance without major cardiac effects in both rats strains. In contrast, the agent reduced vascular resistances only in the SHR; and this was achieved with dilation of both the afferent and efferent glomerular arterioles. These latter changes may be beneficial in the hypertensive state since glomerular hyperfiltration may be reduced, thereby providing a beneficial protective effect on the glomeruli.     

Efferent glomerular arteriolar constriction: a possible intrarenal hemodynamic defect in hypertension

A variety of mechanisms involving the kidney subserve the control of arterial pressure and the development and maintenance of hypertension. The precise and direct delineation of intrarenal hemodynamic mechanisms has been possible only by micropuncture techniques. Since these methods can be used only in the anesthetized animal, intrarenal hemodynamic assessment in conscious intact experimental animals or patients with essential hypertension must be indirect. Using indirect methods, calculated pressures in our laboratory have demonstrated differences in intrarenal hemodynamics between SHR and normotensive WKY rats, notably enhanced responsiveness of the efferent arteriole to alpha adrenergic agonist stimulation. When the calcium antagonist diltiazem was administered to the SHR or to patients with essential hypertension, it effected an increased renal blood flow and a well-maintained glomerular filtration rate without hyperfiltration. These indirect data suggest that there may be an efferent arteriolar abnormality in genetically mediated hypertension that may be reversed with certain calcium antagonists.     

N- and L-type calcium channel antagonist improves glomerular dynamics,reverses severe nephrosclerosis,and inhibits apoptosis and proliferation in an l-NAME/SHR model

OBJECTIVE : To determine the responses of the new dihydropyridine N- and L-type calcium antagonist, cilnidipine, on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathology in an Nomega-nitro-l-arginine methylester spontaneously hypertensive rat (l-NAME/SHR) model of nephrosclerosis. METHODS : Five groups of 20-week-old male SHR were studied using renal micropuncture techniques and histopathological analyses: group 1, control; group 2, cilnidipine (10 mg/kg per day) by gavage, for 3 weeks; group 3, l-NAME (50 mg/l) in drinking water, for 3 weeks; group 4, combination of l-NAME and cilnidipine, for 3 weeks; group 5, l-NAME for 3 weeks, followed by cilnidipine for a subsequent 3 weeks. RESULTS : Cilnidipine significantly reduced mean arterial pressure, total peripheral resistance and renal vascular resistance, while increasing effective renal blood flow and glomerular filtration rate (P < 0.01) in l-NAME/SHR. These hemodynamic changes were associated with significantly increased single nephron glomerular filtration rate (SNGFR) and plasma flow (SNPF) and decreased afferent glomerular arteriolar resistances when cilnidipine was used alone, and with increased SNGFR and SNPF, but decreased glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary protein excretion, serum creatinine and uric acid concentrations (at least P < 0.05) in l-NAME-exacerbated SHR nephrosclerosis. In addition, glomerular and arteriolar injuries were markedly reversed (both P < 0.01), and glomerular apoptosis and cellular proliferation were inhibited and associated with glomerular tuft enlargement and an increase in cell number. CONCLUSION : Cilnidipine not only prevented, but reversed, the severe renal hemodynamic and glomerular dynamic changes, including apoptosis and glomerular cellular proliferation, in l-NAME/SHR-exacerbated nephrosclerosis. This dual-channel calcium antagonist thus exerted renoprotective pathophysiological effects in the l-NAME/SHR.     

Pressure-induced vasoconstriction of renal microvessels in normotensive and hypertensive rats. Studies in the isolated perfused hydronephrotic kidney

The capacity of small arteries to respond to increased intravascular pressure may be altered in hypertension. In the kidney, hypertension is associated with a compensatory shift in the autoregulatory response to pressure. To directly determine the effects of established hypertension on the renal microvascular response to changes of perfusion pressure, we evaluated pressure-induced vasoconstriction in hydronephrotic kidneys isolated from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Vessel diameters of interlobular arteries (ILAs) and afferent and efferent arterioles were determined by computer-assisted videomicroscopy during alterations in renal arterial pressure (RAP) from 80 to 180 mm Hg. Increased RAP induced a pressure-dependent vasoconstriction in preglomerular vessels (afferent arterioles and ILAs), but not in postglomerular vessels (efferent arterioles). The calcium antagonist nifedipine prevented pressure-induced afferent arteriolar vasoconstriction with a similar half-maximal inhibitory concentration (IC50) (WKY, 63 +/- 27 vs. SHR, 60 +/- 32 nM). The pressure-activation curves for ILAs in SHR and WKY were similar. In contrast, the pressure-activation curve for afferent arterioles in SHR kidneys exhibited a rightward shift, which was observed at every segment of the afferent arteriole (i.e., near ILA, at midportion, and near glomerulus). These findings demonstrate that the ILA and the afferent arteriole both possess the ability to constrict in response to increased pressure, whereas this property is lacking in the efferent arteriole. Hypertension was associated with a compensatory shift in the pressure response of the afferent arteriole, such that higher RAPs were required to elicit vasoconstriction in this vessel.     

Ouabain Produces Diverse Excitatory Effects on Afferent Baroreceptor Nerve Activity in SHR and WKY Animals

The effect of acute ouabain treatment was evaluated on afferent baroreceptor nerve activity in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Under urethane anesthesia (1.2 mg/Kg) the discharge of the recurrent laryngeal nerve was utilized as index of arterial baroreceptor activity (BNA) in rats with the ipslateral vagus cut at a proximal level. The ouabain (30 μg, i.v.) treatment produced an excitatory effect on BNA without changes in basal arterial pressure in both groups studied. This effect was larger in SHR (92±10%) than WKY (37±4%, P < 0.01)

The arterial pressor response to phenylephrine was similar in both SHR and WKY before (20±1 and 22±1.2 mmHg) and after (18±1.4 and 20±2 mmHg, respectively) ouabain. The BNA under phenylephrine-induced peaks of high arterial pressure was significantly higher in SHR (61±15%) than in WKY (41±5% P < 0.01) but after ouabain treatment the opposite was observed (31±5 vs. 61±4% P < 0.01). The inhibitory effects of sodium nitroprusside on arterial pressure and BNA were similar in SHR and WKY groups both before and after the ouabain treatment

These data indicate an excitatory effect of ouabain on baroreceptor nerve activity in normotensive and markedly in hypertensive rats which could contribute to the reflex arterial pressure regulation, besides the known inotropic action on the heart     

Abnormal renal vascular responses to dipyridamole-induced vasodilation in spontaneously hypertensive rats

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg. kg(-1). min(-1)) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by approximately 20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.     

Renal function of conscious spontaneously hypertensive rats

Renal clearance studies were performed in conscious 13-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before and during volume expansion by intravenous infusion of isotonic saline. Mean arterial pressure and filtration fraction were greater in SHR, whereas fractional and absolute excretion of sodium and water, glomerular filtration rate, and renal plasma flow in SHR and WKY were not statistically different. This was the case during hydropenia and volume expansion. We did not observe as exaggerated natriuresis after intravenous loading when unanesthetized SHR were compared with the response of WKY. These observations suggest that the kidneys of genetically hypertensive rats of the Okamoto-Aoki strain have adapted to an elevated renal perfusion pressure or that hypertension is required to normalize renal function so that excretion is appropriately matched with intake.     

Impaired renorenal reflexes in spontaneously hypertensive rats

In normotensive Sprague-Dawley rats stimulation of renal mechanoreceptors and chemoreceptors by increasing ureteral pressure and retrograde ureteropelvic perfusion with 0.9 M NaCl results in a contralateral inhibitory renorenal reflex response with contralateral diuresis and natriuresis. Since efferent renal nerve activity is increased in spontaneously hypertensive rats (SHR) and renal denervation delays the onset of hypertension in SHR in association with increased diuresis and natriuresis, the present study was undertaken to examine whether renorenal reflexes were altered in SHR compared with normotensive Wistar-Kyoto rats (WKY). In WKY mean arterial pressure was 113 +/- 2 mm Hg and remained unchanged during renal mechanoreceptor and chemoreceptor stimulation. Increasing ureteral pressure 35 mm Hg increased ipsilateral afferent renal nerve activity 4.5 +/- 1.7 resets/min, decreased contralateral efferent renal nerve activity 3.2 +/- 0.8 resets/min, and increased contralateral urine flow rate 33 +/- 4% and urinary sodium excretion 49 +/- 8%. Similarly, retrograde ureteropelvic perfusion with 0.9 M NaCl increased ipsilateral afferent renal nerve activity 2.5 +/- 0.6 resets/min, decreased contralateral efferent renal nerve activity 2.4 +/- 1.1 resets/min, and increased contralateral urine flow rate 39 +/- 5% and urinary sodium excretion 38 +/- 8%. Stimulating renal mechanoreceptors and chemoreceptors to the same extent in SHR failed to increase ipsilateral afferent renal nerve activity, decrease contralateral efferent renal nerve activity, and produce a contralateral diuresis and natriuresis. It is concluded that renorenal reflexes are impaired in SHR. Failure of ipsilateral afferent renal nerve activity to increase during renal mechanoreceptor and chemoreceptor stimulation indicates a peripheral defect at the level of the renal sensory receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

DOCA-salt induced malignant hypertension in spontaneously hypertensive rats

DOCA-salt hypertension was produced in 10 male 10-week-old normotensive Wistar-Kyoto (WKY) rats receiving deoxycorticosterone acetate (DOCA; 100 mg/kg, subcutaneous pellet) and 1% NaCl drinking water and was compared with data from 10 age- and sex-matched WKY receiving normal tap water (C). These data were also compared with spontaneously hypertensive (SHR) rats similarly treated. After 10 weeks on these programmes, systemic and regional haemodynamics were determined in conscious rats using microsphere techniques. DOCA-salt treatment increased mean arterial pressure (MAP), total peripheral resistance index (TPRI), cardiac and renal weights in both WKY and SHR. In contrast to SHR (C), the SHR (DOCA) demonstrated more severe MAP elevation (204 +/- 4 versus 185 +/- mmHg; P less than 0.01), more severe systemic and regional (especially renal) vasoconstriction, and malignant vasculitis associated with azotaemia and hyperuricaemia. The hyperuricaemia was related inversely to renal blood flow (r = -0.74; P less than 0.01) and directly to renal vasoconstriction (r = 0.65; P less than 0.05) in SHR (DOCA). These data suggest that in both WKY and SHR, DOCA and salt produced marked cardiovascular changes and SHR rats developed malignant hypertension.     

Intrarenal hemodynamics in patients with essential hypertension

Intrarenal hemodynamics were estimated clinically in essential hypertension. Two-week studies were performed in 30 patients with essential hypertension who were given a regular sodium diet in the first week and a sodium-restricted diet in the second week. Intrarenal hemodynamic parameters such as afferent arteriolar (preglomerular) resistance, efferent arteriolar resistance, and glomerular hydrostatic pressure were calculated from renal clearances and plasma total protein concentration measured on the last day of the regular sodium diet. Calculations were based on Gomez's equations with the assumption that the gross filtration coefficient of glomerular capillaries was normal. The increase in afferent arteriolar resistance (8,100 +/- 500 dyne.sec.cm-5) was significantly correlated with an elevation in mean arterial pressure (120 +/- 2 mm Hg), whereas glomerular pressure (56 +/- 1 mm Hg) and efferent arteriolar resistance (2,500 +/- 100 dyne.sec.cm-5) remained normal. The renal function curve (pressure-natriuresis relation) was drawn by plotting urinary sodium excretion on the y axis as a function of mean arterial pressure on the x axis, both of which were measured on the last 3 days of each week. The extrapolated x intercept (107 +/- 2 mm Hg) of the renal function curve was strongly correlated in a 1:1 fashion with the sum of the arterial pressure drop from the aorta to the renal glomeruli plus the opposing pressures against glomerular filtration at glomeruli (r = 0.7, p less than 0.001) on the regular sodium diet, suggesting that the difference between mean arterial pressure on the regular sodium diet and the extrapolated x intercept represented the effective filtration pressure across the glomerular capillaries on the regular sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.     

Hemodynamic Effects of Prolonged Treatment with Diltiazem in Conscious Normotensive and Spontaneously Hypertensive Rats

To determine systemic and regional hemodynamic effects of prolonged treatment with the calcium antagonist diltiazem (30 mg/kg twice daily by gastric gavage, for 3 weeks), data from 12 Wistar-Kyoto (WKY) and 10 spontaneously hypertensive (SHR) rats were compared with those obtained from 11 WKY and 10 SHR controls treated with the vehicle. Systemic and regional hemodynamics were determined in the conscious, unrestrained state using the reference sample microsphere method. Mean arterial pressure (MAP) decreased in SHR by 9% (183±4 to 167±4 mmHg; p < 0.05) but remained unchanged in WKY, while cardiac index (CI) tended to decrease in both strains; heart rate fell by 15% only in WKY (481·;10 to 354·13 beats/min; p < 0.05). Total peripheral resistance index (TPRI) tended to decrease in SHR but to increase in WKY. Organ blood flow in SHR decreased in skin and splanchnic organs, while organ vascular resistance decreased in brain and increased in splanchnic organs. In contrast, organ blood flow increased in heart and decreased in kidneys and skin of the WKY, while organ vascular resistance decreased in heart and increased in kidneys and skin. Thus, diltiazem produced nonuniform and different hemodynamic effects in the two strains. Further, diltiazem did not alter the cardiac mass in either rat strain. We therefore conclude that diltiazem demonstrated a mild hypotensive effect in SHR that was associated with slight reductions in CI and TPRI, the latter being non-uniformly distributed in the component organ circulations.     

Impaired nitric oxide-independent dilation of renal afferent arterioles in spontaneously hypertensive rats.

Sustained hypertension alters vasomotor regulation in various vascular beds. We studied whether nitric oxide (NO)-dependent and NO-independent vasodilator mechanisms are altered in renal microvessels in hypertension. To directly visualize the renal microcirculation, the isolated perfused hydronephrotic rat kidney model was used. After pretreatment with indomethacin (100 micromol/l), afferent arterioles were constricted by norepinephrine (NE) or by increasing renal arterial pressure (i.e., myogenic constriction; from 80 to 180 mmHg). Acetylcholine (ACH) was then added, and the renal microvascular response was assessed by computer-assisted video image analysis. A similar protocol was conducted in the presence of nitro-L-arginine methylester (L-NAME; 100 micromol/l). During NE constriction, ACH caused dose-dependent and sustained vasodilation of the afferent arteriole, similar in magnitude in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the presence of L-NAME, ACH (0.01-1 micromol/l) elicited only transient dilation, and the degree of vasodilation was very low in SHR. During myogenic constriction, afferent arterioles from WKY and SHR kidneys responded to ACH with only transient vasodilation, which was unaffected by NO inhibition; the transient vasodilative responses elicited by ACH (0.1-1 micromol/l) were smaller in SHR than in WKY. In conclusion, ACH has both sustained and transient vasodilative effects on the afferent arteriole. Sustained vasodilation is attributed to NO generation, which is similar in WKY and SHR. In contrast, transient vasodilation, mediated by NO-independent vasodilator factors, is impaired in SHR. Deranged vasodilatory mechanisms in hypertension may disturb the renal microcirculation, which may result in renal injury.     

Effect of denervation on the afferent arteriole in the SHR

To study the role the renal nerves may play in the hypertension of the SHR, we conducted a morphometric study of the afferent arteriole of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) which were subjected to renal denervation (or sham-operation). Methacrylate casts were made of the renal vasculature after perfusion fixation with glutaraldehyde. These vascular casts were then examined and measurements made with the scanning electron microscope (SEM). Afferent arterioles of the denervated SHR were dilated in comparison to the sham-operated SHR, but there was no difference between the afferent arteriolar diameters of the 2 groups of WKYs. However, the afferent arteriolar diameters of the SHR (either group) were smaller than those of the WKY. Renal denervation caused a reduction in systolic blood pressure compared to sham-operated in both strains of rat. We concluded that the dilation changes of afferent arterioles of denervated SHRs may be related to renal autoregulation resulting from the decreased blood pressure. However, the effect of the loss of sympathetic innervation of the arterioles cannot be ruled out.     

Effects of low-dose chronic diltiazem treatment on hemodynamic changes in spontaneously hypertensive rats

The effects of long-term diltiazem treatment on hemodynamic and cardiovascular characteristics were investigated in young spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and their respective untreated controls. The drug was administered to treated rats over a period of 24 weeks. Body weight, left ventricular weight, mean arterial pressure (MAP), heart rate, max dp/dt or maximum velocity of the contractile element (Vmax) were not significantly different in diltiazem-treated SHR and untreated SHR. In diltiazem-treated SHR, cardiac index (CI) and stroke volume index (SI) were significantly increased and total peripheral resistance and the index of left ventricular compliance (delta P/delta V) were significantly decreased compared with untreated SHR. Left ventricular pumping ability in treated SHR was higher than that in untreated SHR, despite the low dose of diltiazem given. However, there was no significant difference between treated and untreated WKY. Long-term diltiazem treatment did not affect left ventricular function or biochemical properties in SHR and WKY. These data suggest that long-term diltiazem treatment improves pump function in SHR without changing blood pressure.     

Impaired prostaglandin E(2)/prostaglandin I(2) receptor-G(s) protein interactions in isolated renal resistance arterioles of spontaneously hypertensive rats

The protective effect of vasodilator agents linked to the cAMP pathway is less effective for buffering the vasoconstrictor effect of angiotensin II in young animals with genetic hypertension. To determine the underlying cellular mechanism, experiments were performed on freshly isolated preglomerular resistance arterioles obtained from kidneys of 7-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Specific high-affinity saturable binding of (3)H-prostaglandin (PG) E(2) revealed 1 receptor class in renal microvessels; PGE(2) receptor density was similar in SHR and WKY (106 versus 115 fmol/mg; P>0.8), as was receptor affinity (3.6 versus 3.5 nmol/L; P>0.7). Basal cAMP activity was similar in renal arterioles from SHR and WKY. A major finding was that PGE(2), PGI(2), and isoproterenol produced weaker stimulation of cAMP formation in arteriolar cells of SHR (P<0.02). In contrast, GTPgammas and forskolin stimulated cAMP generation to a similar degree in both rat strains, which suggests normal adenylate cyclase activity in hypertension-prone SHR. Immunoblots revealed the presence of 3 classes of G proteins (G(s), G(i), and G(q)) in preglomerular arterioles. The relative amounts of discernible G-protein alpha-subunits in renal resistance vessels did not differ between SHR and WKY. These results extend previous in vivo studies of abnormal renal vascular reactivity in SHR and more directly localize defective coupling of the prostaglandin and beta-adrenergic receptors to a stimulatory G protein and cAMP production in freshly isolated preglomerular arteriolar cells of young SHR. This dysfunction may be due to an abnormal interaction between prostaglandin receptors and G(s) protein that leads to inefficient coupling of initiating steps in the cAMP-protein kinase A cascade during the development of hypertension.     

Renorenal reflexes present in young and captopril-treated adult spontaneously hypertensive rats

In normotensive Sprague-Dawley rats and Wistar-Kyoto (WKY) rats stimulation of renal mechanoreceptors or chemoreceptors by increasing ureteral pressure or renal pelvic perfusion with 0.9 M NaCl results in a contralateral inhibitory renorenal reflex response with contralateral diuresis and natriuresis. However, in 14-15-week-old spontaneously hypertensive rats (SHR) renal sensory receptor stimulation failed to elicit a contralateral inhibitory renorenal reflex response. The present study was performed to examine whether the lack of a renorenal reflex response in SHR was related to elevated arterial pressure by studying the responses to renal sensory receptor stimulation in 5-6-week-old SHR and in 12-16-week-old SHR that had been treated with captopril from 3 weeks of age to prevent the development of hypertension. In 5-6-week-old SHR, mean arterial pressure was 113 +/- 3 mm Hg. Graded increases of ureteral pressure of 15 and 29 mm Hg resulted in graded increases in ipsilateral afferent renal nerve activity of 57 +/- 22% and 120 +/- 38%. Contralateral urinary sodium excretion increased from 0.26 +/- 0.06 to 0.35 +/- 0.07 mumol/min/g and from 0.36 +/- 0.08 to 0.46 +/- 0.11 mumol/min/g, respectively. In captopril-treated SHR, mean arterial pressure was 109 +/- 3 mm Hg. Increasing ureteral pressure by 34 mm Hg increased ipsilateral afferent renal nerve activity 65 +/- 21% and contralateral urinary sodium excretion from 1.28 +/- 0.24 to 1.53 +/- 0.30 mumol/min/g. Similar results were produced by renal chemoreceptor stimulation. It is concluded that renal sensory receptor stimulation results in a contralateral inhibitory renorenal reflex response in 5-6-week-old SHR and in SHR treated with captopril to prevent the development of hypertension. These results suggest that the previously demonstrated lack of a renorenal reflex response to renal sensory receptor stimulation in hypertensive SHR is related to the maintenance of hypertension.     

Differential effects of T- and L-type calcium antagonists on glomerular dynamics in spontaneously hypertensive rats.

To determine whether there is a difference in the effects of T- and L-type calcium antagonists on systemic, renal, and glomerular hemodynamics, the pathological changes of N(G)-nitro-L-arginine methyl ester (L-NAME)-exacerbated nephrosclerosis and clinical alterations were investigated in spontaneously hypertensive rats (SHR). Seven groups of 17-week-old male SHRs were studied: Group 1, control; Group 2, mibefradil, 50 mg. kg(-1). d(-1); Group 3, L-NAME in drinking water, 50 mg/L; Group 4, L-NAME (50 mg/L) plus mibefradil (50 mg. kg(-1). d(-1)); Group 5, L-NAME (50 mg/L) plus amlodipine (10 mg. kg(-1). d(-1)); Group 6 and 7, L-NAME (50 mg/L) for 3 weeks followed by mibefradil (50 mg. kg(-1). d(-1)) or amlodipine (10 mg. kg(-1). d(-1)), respectively, for the subsequent 3 weeks. Both the T- and L-channel calcium antagonists similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances and the ultrafiltration coefficient (P<0.01). Furthermore, the histopathological glomerular and arterial injury scores and urinary protein excretion were also significantly improved (P<0.01), and left ventricular and aortic masses were significantly diminished in all treated groups. Both drugs, mibefradil and amlodipine, had effects of increasing the single-nephron glomerular filtration ratio (SNGFR), and single-nephron plasma flow (SNPF), and of reducing glomerular afferent arteriolar resistance and urinary protein excretion. Thus, the T-type (mibefradil) and L-type (amlodipine) calcium antagonists each prevented and reversed the pathophysiological alterations of L-NAME-exacerbated hypertensive nephrosclerosis in SHR. The T-type calcium antagonist (mibefradil) seemed to have been more effective than the L-type amlodipine antagonist and it produced a greater reduction in afferent arteriolar resistance while preserving SNGFR.