Skeletal muscle vasoconstriction produced by prostaglandin synthesis inhibitors; dependence on pump perfusion

A comparison was made of the effect of prostaglandin synthesis inhibitors (PGSI) on systemic blood pressure and hindlimb muscle vascular resistance of anesthetized dogs under different experimental conditions. When muscle blood flow was monitored using an extracorporeal or noncannulating electromagnetic blood flow probe, indomethacin (5 mg/kg i.v.) increased blood pressure slightly, but did not change vascular resistance. Administration of PGSI (indomethacin, meclofenamate, or naproxen, 5 mg/kg i.v.) after 2 hr of pump perfusion of the hindlimb caused a 22% increase in blood pressure, and 39% increase in vascular resistance 30 min afterwards. When administered immediately after instituting pump perfusion, indomethacin caused no significant change in blood pressure or vascular resistance at the 30 min interval, but at 60 min vascular resistance was increased. A similar vasoconstrictor response to indomethacin was obtained when it was infused in a lower dose intraarterially to the hindlimb, or when given i.v. after ligation of the renal pedicles. The results indicate that pump perfusion results in elaboration of a nonrenal prostaglandin(s) which maintains a vasodilator influence on the skeletal muscle vascular bed.     

Dose effect of captopril on renal hemodynamics and proteinuria in conscious, partially nephrectomized rats

The effect of varying doses of captopril, an angiotensin I-converting enzyme inhibitor, on renal hemodynamics, systemic arterial pressure, and the progression of chronic renal disease in conscious, three-quarter nephrectomized adult male Sprague-Dawley rats was studied. Six weeks following nephrectomy (Week 0), rats were randomly divided into five groups. Group 2 (n = 8), 3 (n = 8), 4 (n = 9), and 5 (n = 5) were given 5, 10, 20, and 40 mg/kg captopril, respectively, daily in drinking water. Group 1 (n = 7) and sham-operated controls (n = 7) were given water only. On Weeks -6, 0, 2, and 4, renal function was assessed by 24-hr urinary protein excretion and plasma creatinine. Systolic blood pressure was measured at these times by the tail cuff method. Following Week 4, glomerular filtration rate and effective renal plasma flow were measured in conscious rats by single injection clearance of [3H]inulin and [14C]tetraethylammonium bromide, respectively. Group 1 had significantly higher (P less than 0.05) 24-h urinary protein excretion, plasma creatinine, and systolic pressure compared with Group 5 and controls by Week 4, whereas values for these parameters for Groups 2-4 ranged between these extremes. Although systolic pressures were not significantly different (P greater than 0.05), Group 2 had significantly lower proteinuria than Group 1 (P less than 0.05) at Week 4. Total kidney glomerular filtration rate was similarly decreased in Groups 1-5 compared with control rats. Total kidney effective renal plasma flow was higher in captopril-treated groups than in Group 1, whereas systolic blood pressure was similar or lower, indicating that captopril reduced renal vascular resistance. Furthermore, unlike Groups 1-3, the groups receiving higher doses of captopril (4 and 5) did not develop anemia associated with chronic renal disease. In conclusion, captopril attenuated renal functional deterioration in a dose-related manner. The effect on proteinuria was evident at low doses of captopril which did not significantly reduce systemic blood pressure and was accompanied by an increase in effective renal plasma flow and a decrease in renal vascular resistance.     

Prostaglandins and renal function II. The effect of prostaglandin inhibition on autoregulation of blood flow in the intact kidney of the dog

In order to evaluate the effect of prostaglandin release on renal autoregulation in the intact kidney of the dog, pressure-flow curves were obtained before and after the administration of either indomethacin or meclofenamate, two potent prostaglandin synthetase inhibitors. After drug administration renal venous prostaglandin E decreased in each of eight studies with a mean change from 286 to 141 pg/ml (p < .001). In addition, prostaglandin inhibition was associated with a 31 percent decrease in renal blood flow and a 58 percent increase in renal resistance. Yet, as renal perfusion pressure was decreased by aortic constriction, the change in flow per pressure reduction and the percent change in renal resistance were not significantly different after prostaglandin inhibition when compared to control values in the same animals. The magnitude of the pressure range over which autoregulation was maintained was also similar in the two groups although both the initial and lowest level of autoregulation were slightly higher after prostaglandin inhibition. It is concluded that the administration of these prostaglandin synthetase inhibitors does not significantly impair renal autoregulation in the intact dog kidney.     

Lack of renal vasodilation during intrarenal infusion of synthetic atriopeptin II in conscious intact SHR

Synthetic atriopeptin II (APII) was infused directly into the right renal artery of intact conscious SHR at rates of 0.25-1 microgram/kg/min, while simultaneously measuring blood pressure (MAP) and selected regional blood flows. The latter were measured using chronically implanted miniaturized Doppler flowprobes that were placed on the right and left renal artery, superior mesenteric artery and abdominal aorta. The effects of intrarenally (i.r.) infused APII on these vascular beds were compared to the effects of the same amounts of APII given intravenously (i.v.) in the same SHR. I.r. and i.v. infusions caused similar reductions of MAP and all four blood flows. Also effects on calculated resistances were comparable, implying that resistance increased most in the mesentery and least in the two kidneys. The increase in right renal resistance during i.v. infusions of APII was not different from the effect during i.r. infusions. Also, during i.r. infusions into the right kidney, effects on the left and right kidney were not different. Our observations suggest that synthetic APII has no direct effects on the renal vasculature of intact conscious SHR.     

Pressor responsiveness in renal prehypertensive rabbits with a denervated kidney

Norepinephrine was infused iv at several doses into four groups of conscious rabbits (six per group), and the pressor responses were recorded. The groups were 3-day sham-operated rabbits; 3-day, two-kidney rabbits with unilateral renal artery stenosis (RAS); 3-day, two-kidney rabbits with unilateral renal denervation; and 3-day, two-kidney rabbits with unilateral renal denervation plus RAS of the denervated kidney. The rabbits with RAS of an innervated kidney and those with RAS of a denervated kidney had the same pressor responses to norepinephrine, which were greater than the pressor responses in the sham-operated rabbits or in the rabbits with a denervated kidney but without RAS. Four additional groups of similarly prepared rabbits were infused with norepinephrine at 800 ng/min/kg body wt, and mean arterial pressure and cardiac output were determined before and during norepinephrine infusion. The rabbits with RAS of an innervated or of a denervated kidney had greater increases in total peripheral resistance as well as in mean arterial pressure during norepinephrine infusion than did the two groups of rabbits without RAS. This indicated that the rabbits with RAS also had increased vascular responses to norepinephrine. The concentration of norepinephrine in six denervated kidneys was extremely low as compared to that of six innervated kidneys. Because renal denervation did not diminish pressor and vascular hyperresponsiveness in 3-day RAS rabbits, the signal that originates in the kidney following RAS and that results ultimately in pressor and vascular hyperresponsiveness is not mediated by renal nerves.     

Critical opening pressure and reactivity of tail vessels in conscious hypertensive rats.

The possible role of increased vascular reactivity in the mechanism of experimental hypertension was studied by measurements of the critical opening pressure (COP) of tail vessels in conscious rats. In hypertension induced by administration of desoxycorticosterone acetate (DOCA) and replacement of the drinking water by 1% NaCl solution (DOCA-NaCl hypertension), and in one-kidney Goldblatt renovascular hypertension, the raised level of blood pressure was associated with an increased COP of the tail vessels when measured both before and after ganglionic blockade. In rats treated with either DOCA alone or 1% NaCl alone there was no significant increase in systolic blood pressure (SBP) or COP relative to the corresponding controls. In all four experimental series intravenous infusion of angiotensin or norepinephrine in conscious ganglion-blocked rats produced dose-dependent increases in SBP and COP. In DOCA-NaCl hypertensive rats but not in renovascular hypertensives, nor in rats treated with DOCA alone or 1% NaCl alone, the increase in COP for a given increment in dose of angiotensin or norepinephrine was significantly greater than in the control rats. It is concluded that in DOCA-NaCl hypertension there is a true increase in the reactivity of the smooth muscle of the resistance vessels to angiotensin and norepinephrine. In renovascular hypertension this is not the case and other factors must therefore be involved in causing the increased blood pressure and COP.     

The influence of adrenal vein occlusion on whole-kidney hemodynamics in the spontaneously hypertensive rats.

It has been shown that occlusion of the adrenal vein causes an increase in renal vascular resistance in the ipsilateral kidney in Wistar Kyoto rats (WKY). The most probable mechanism of this phenomenon is the direct inflow of adrenal catecholamines to the kidney by the adrenal renal portal circulation (ARPC). As the number of vessels of the ARPC is bigger and the tonic sympathetic activity is higher in spontaneously hypertensive rats (SHR), the aim of the current study was to compare the effect of adrenal vein occlusion on renal vascular resistance between SHR and WKY. Mean arterial blood pressure and renal blood flow (RBF) were measured and renal vascular resistance (RVR) was calculated before and after closure of the adrenal vein. Occlusion of the adrenal vein significantly reduced RBF and increased RVR in both strains of rats. The rise of the RVR was significantly higher in SHR than in WKY. Therefore we assume that the hemodynamic responsiveness of the kidney due to increase in blood flow through ARPC is greater in SHR and may contribute to the development of arterial hypertension in this strain of rat.     

Cardiovascular responses to V1-vasopressinergic antagonism in conscious versus anesthetized rats

Experiments were performed to compare the possible effect of endogenous arginine vasopressin on renal hemodynamics between anesthetized, surgically stressed rats and conscious rats. Animals were instrumented with arterial and venous catheters as well as with a pulsed Doppler flow probe on the left renal artery. The rats were studied under the following conditions: (1) conscious and unrestrained; (2) anesthetized only; (3) anesthetized with minor surgical stress; and (4) anesthetized with major surgical stress. Two anesthetic agents were also compared, a mixture of ketamine (110 mg/kg i.m.) and acepromazine (1 mg/kg i.m.), and sodium pentobarbital (50 mg/kg i.p.). Baseline mean arterial blood pressure was significantly higher in pentobarbital-anesthetized rats following surgical stress compared with conscious animals, but blood pressure was not affected by ketamine-acepromazine anesthesia. After baseline measurements of blood pressure, heart rate, and renal blood flow, a specific V1-vasopressinergic antagonist (d(CH2)5Tyr(Me) arginine vasopressin, 10 mg/kg i.v.) was administered to each group. Mean arterial blood pressure, heart rate, and renal blood flow were monitored for an additional 15 min. Mean arterial blood pressure and renal blood flow decreased after V1 antagonism in ketamine-acepromazine-anesthetized rats with major surgical stress, but were not affected in pentobarbital-anesthetized animals. Heart rate and renal vascular resistance were not affected following V1 blockade with either anesthetic agent. These data suggest that arginine vasopressin plays a role in maintaining blood pressure and renal perfusion in ketamine-acepromazine-anesthetized rats following surgical stress, but does not have a significant effect on renal hemodynamics under pentobarbital anesthesia.     

Transgenic mice over-expressing ET-1 in the endothelial cells develop systemic hypertension with altered vascular reactivity

Endothelin-1 (ET-1) is a potent vasoconstrictor involved in the regulation of vascular tone and implicated in hypertension. However, the role of small blood vessels endothelial ET-1 in hypertension remains unclear. The present study investigated the effect of chronic over-expression of endothelial ET-1 on arterial blood pressure and vascular reactivity using transgenic mice approach. Transgenic mice (TET-1) with endothelial ET-1 over-expression showed increased in ET-1 level in the endothelial cells of small pulmonary blood vessels. Although TET-1 mice appeared normal, they developed mild hypertension which was normalized by the ET(A) receptor (BQ123) but not by ET(B) receptor (BQ788) antagonist. Tail-cuff measurements showed a significant elevation of systolic and mean blood pressure in conscious TET-1 mice. The mice also exhibited left ventricular hypertrophy and left axis deviation in electrocardiogram, suggesting an increased peripheral resistance. The ionic concentrations in the urine and serum were normal in 8-week old TET-1 mice, indicating that the systemic hypertension was independent of renal function, although, higher serum urea levels suggested the occurrence of kidney dysfunction. The vascular reactivity of the aorta and the mesenteric artery was altered in the TET-1 mice indicating that chronic endothelial ET-1 up-regulation leads to vascular tone imbalance in both conduit and resistance arteries. These findings provide evidence for the role of spatial expression of ET-1 in the endothelium contributing to mild hypertension was mediated by ET(A) receptors. The results also suggest that chronic endothelial ET-1 over-expression affects both cardiac and vascular functions, which, at least in part, causes blood pressure elevation.     

Reversal of renovascular hypertension: role of the renal medulla

The fall in blood pressure, which occurs when renovascular hypertension is corrected surgically, offers a means of elucidating the factors responsible for blood pressure control. When Goldblatt two-kidney, one-clip hypertension in the rat is reversed by unclipping the renal artery, or by removal of the ischaemic kidney, restoration of normal blood pressure is due to a fall in peripheral resistance. This is associated with sodium retention and cannot be modified by inhibition of the renin-angiotensin system. The fall is, however, partially inhibited by chemical removal of the renal medulla by means of 2-bromo-ethylamine hydrobromide. When normal rats are chemically medullectomized, moderate hypertension is produced, which cannot be attributed to the renin-angiotensin system or sodium retention. It is concluded that a renomedullary vasodepressor system is ablated by chemical medullectomy: further, this system plays a role in the surgical correction of Goldblatt hypertension.     

Cyclooxygenase blockers inhibit ethanol-induced pulmonary vasoconstriction in lambs

We investigated the mechanism of ethanol-induced pulmonary vasoconstriction in lambs, by a pharmacological approach. We chronically instrumented 28 lambs to determine whether phentolamine (alpha-block), propranolol (beta-block), promethazine and cimetidine (H1- and H2-block), high-dose indomethacin, or low- and high-dose meclofenamate (cyclooxygenase block) altered the vasoconstriction. Ethanol alone increased pulmonary vascular resistance from 0.14 to 0.49 Torr.ml-1.kg-1.min (U). Only indomethacin (7-8 mg/kg po) and high-dose meclofenamate (7-8 mg/kg iv) abolished the pulmonary vascular response to ethanol infusion. Pulmonary vascular resistance was 0.14 U after ethanol plus indomethacin and was 0.2 U after ethanol plus high-dose meclofenamate (P = NS vs. base line). Low-dose meclofenamate (2 mg/kg) attenuated the vasoconstrictor response. Systemic vascular resistance increased moderately after ethanol and had a similar pattern of inhibition by cyclooxygenase blockade. Cardiac output and heart rate decreased nearly significantly after ethanol (P less than 0.06), a tendency that was also ablated by cyclooxygenase inhibition. Thus the acute cardiocirculatory response to ethanol involves an intact prostaglandin synthase system in lambs. To our knowledge, these data are the first documentation that cyclooxygenase enzyme blockade can eliminate the acute cardiac and vascular effects of ethanol in a whole-animal system.     

Impaired blood flow autoregulation in nonfiltering kidneys: effects of theophylline administration

To investigate blood flow autoregulation in filtering and nonfiltering kidneys, renal blood flow was determined during graded reductions in renal perfusion pressure in seven anesthetized dogs containing both a filtering and nonfiltering kidney. In each dog, one kidney was made nonfiltering by the method of EH Blaine, JO Davis, and RT Witty (Circ Res 27:1081-1089, 1970). Renal perfusion pressure was decreased from 129 to 115, 99, and 83 mm Hg by stepwise constriction of the suprarenal aorta. In filtering kidneys, the maximum decrease in renal perfusion pressure reduced renal blood flow only 20.1% of control whereas renal blood flow of nonfiltering kidneys decreased by 41.0% of control. During aortic constriction, renal vascular resistance of nonfiltering kidneys remained unchanged or slightly increased. These hemodynamic changes were associated with significantly greater autoregulation indices in nonfiltering kidneys. In eight dogs with nonfiltering kidneys, competitive inhibition of adenosine with theophylline (9 mg/kg iv) restored autoregulation of renal blood flow as shown by significant decreases in renal vascular resistance. These data indicate that in the nonfiltering kidney model, autoregulation of renal blood flow is impaired. It is suggested that this impaired autoregulatory response may result from renal ischemia and the vasoconstrictor influence of elevated intrarenal adenosine concentration.     

Antihypertensive and bilateral renal responses to diuretics in 2-kidney, 1-clip Goldblatt hypertensive rats

Experiments were conducted to assess the effect of furosemide or amiloride alone and a combination of both agents on each kidney in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 25). Intravenous infusion of furosemide alone (1.02 mg/kg.hr) significantly reduced the blood pressure by 14 +/- 5 mmHg. There were 6- to 10-fold increases in water, absolute sodium and fractional sodium excretions and a 2-fold increase in potassium excretion in the nonclipped kidney. A smaller but significant increase in the excretory function was also observed in the clipped kidney. There was no significant change in GFR of both kidneys. Indomethacin pretreatment (2 mg/kg) failed to significantly alter the vasodepressor and renal responses to furosemide in both hypertensive and normal rats. Removal of the renal artery clip from the hypertensive rats reduced the blood pressure by 12 +/- 3 mmHg and enhanced the function of the ipsilateral, unclipped kidney. Subsequent administration of furosemide further increased the excretory response. Administration of amiloride alone (2.4 mg/kg.hr) or with furosemide into hypertensive rats reduced the arterial pressure and increased excretion rates of urine flow and urinary sodium. Potassium excretion rate decreased bilaterally in amiloride treated rats but did not alter significantly in rats which received a combination of amiloride and furosemide. These results indicate that diuretics ameliorate the excretory function of both the stenotic kidney and the nonstenotic kidney and that the improvement of the kidney function is independent of prostaglandin. Furthermore, removal of the stenosis accentuates the beneficial effect of diuretics on the kidney.     

Dose-dependent effects of nitric oxide synthase inhibition on systemic and renal hemodynamics in conscious lambs.

The present experiments were carried out to determine the role of nitric oxide in influencing systemic and renal hemodynamics in conscious young sheep. Parameters of cardiovascular function were measured before and for 4 h after intravenous injection of either L-NAME (NG-nitro-L-arginine methyl ester) or D-NAME (N(G)-nitro-D-arginine methyl ester) at doses of 10, 20, or 40 mg/kg in 13 conscious, chronically instrumented young sheep aged 43 +/-5 days. Blood pressure increased and heart rate decreased in a dose-dependent manner following administration of L-NAME. Renal vascular resistance was increased for 10 min following a dose of 10 mg/kg of L-NAME and for 120 min following a dose of 40 mg/kg of L-NAME. The renal vasodilatory response to close arterial injection of 1 microg/kg of acetylcholine was attenuated by L-NAME in a dose-dependent manner. These experiments provide the first information that under normal physiological conditions in conscious young animals, nitric oxide influences systemic and renal hemodynamics.     

Nitrendipine and other calcium entry blockers (calcium antagonists) in hypertension

Nitrendipine is a calcium antagonistic 1,4-dihydropyridine derivative with a pronounced antihypertensive activity in animal experiment. Similar to other calcium entry blockers, nitrendipine decreases blood pressure by lowering the elevated peripheral vascular resistance. However, its long-term effect differs from that of vasodilators such as hydralazine and minoxidil. In contrast to vasodilators, nitrendipine reduces heart hypertrophy in various forms of experimental hypertension in rats. Nitrendipine is highly effective in normalizing blood pressure, reducing heart hypertrophy, and preventing mortality in salt-related hypertension (two-kidney renal hypertension, salt-induced hypertension in Dahl rats), which are rather refractory to the effect of vasodilators. Nitrendipine reduces renovascular resistance in spontaneously hypertensive rats but has no effect on that of normotensive rats. In conscious renal hypertensive dogs, nitrendipine decreases blood pressure more than does hydralazine. The reflex tachycardia is more pronounced after hydralazine than after nitrendipine; blood pressure decrease is greater and the duration of the effect is longer than that of nifedipine. Nitrendipine is thus predicted as an effective drug for antihypertensive monotherapy.     

Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance.

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.     

Sympathetic-renal interaction in chronic arterial pressure control

The effects of neonatal sympathectomy of donors or recipients on posttransplantation arterial pressure were investigated in spontaneously hypertensive rats (SHR) by renal transplantation experiments. Conscious mean arterial pressure (MAP) and renal vascular resistance were 136 +/- 1 mmHg and 15.5 +/- 1.2 mmHg x ml(-1) x min x g in sympathectomized SHR (n = 8) vs. 158 +/- 4 mmHg (P < 0.001) and 20.8 +/- 1.1 mmHg x ml(-1) x min x g (P < 0.05) in controls (n = 10). Seven weeks after transplantation of a kidney from neonatally sympathectomized SHR donors, MAP in SHR recipients (n = 10) was 20 mmHg lower than in controls transplanted with a kidney from hydralazine-treated SHR (n = 10) (P < 0.05) associated with reduced sodium sensitivity of MAP. Neonatal sympathectomy also lowered MAP in F1-hybrids (F1H; SHR x Wistar-Kyoto rats). Within 6 wk after transplantation, renal grafts from untreated SHR increased MAP by 20 mmHg in sympathectomized F1H (n = 10) and by 35 mmHg in sham-treated F1H (n = 8) (P < 0.05). Neonatal sympathectomy induces chronic changes in SHR kidney function leading to a MAP reduction even when extrarenal sympathetic tone is restored. Generalized reduction in sympathetic tone resets the kidney-fluid system to reduced MAP and blunts the extent of arterial pressure rise induced by an SHR kidney graft.     

Prostaglandin modulation of the vascular effects of vasopressin in the conscious rat

Experiments were performed on conscious, male Sprague-Dawley rats to determine whether cyclooxygenase inhibition affects the pressor response to exogenous vasopressin. The rise in arterial blood pressure was tested in response to 1.0, 2.5, 5.0, and 12.5 mU synthetic arginine vasopressin both before and following cyclooxygenase inhibition with either meclofenamate or the structurally dissimilar inhibitor ibuprofen. In addition, time control experiments were also performed where only the saline vehicle for the drugs was administered. In all animals tested, the increase in arterial pressure in response to the highest three concentrations of vasopressin was greater following cyclooxygenase inhibition than before, while the saline vehicle had no effect. The baroreceptor-mediated bradycardia accompanying the rise in blood pressure was variable, but unaffected by meclofenamate or ibuprofen. It is concluded that vasodilator prostaglandins are released in response to pressor levels of vasopressin, which act to modulate the pressor response of the peptide.     

Evidence for an intrarenal renin-angiotensin system in the rainbow trout, Oncorhynchus mykiss

Physiological and molecular approaches were used to investigate the existence of an intrarenal renin-angiotensin system (RAS) in rainbow trout. Inhibition of angiotensin-converting enzyme by captopril (5 x 10(-4 )M) rapidly decreased vascular resistance of the trunk of the trout, perfused at 19 mmHg, resulting in an increased perfusate flow rate and a decreased intrarenal dorsal aortic pressure. A profound diuresis occurred in the in situ perfused kidney and reflected both increased glomerular filtration rates and decreased water reabsorption (osmolyte reabsorption was unchanged). Renal and vascular parameters recovered once captopril treatment was stopped. Diuretic and vascular effects of captopril on the in situ trout kidney concur with an inhibition of known vasoconstrictor and antidiuretic actions of angiotensin II. However, at a higher perfusion pressure (28 mmHg), captopril had no effect on intrarenal aortic pressure or perfusate and urine flow rates, suggesting that the trout intrarenal RAS is activated by low perfusion pressures/flows. Existence of the renal RAS in trout was further supported by evidence for angiotensinogen gene expression in kidney as well as liver.     

Antihypertensive profile of the angiotensin-converting enzyme inhibitors CI-906 and CI-907

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.