Exaggerated natriuresis after selective AT1 receptor blockade in Dahl salt-sensitive rats.

Salt-sensitive individuals are susceptible to develop hypertension when exposed to high salt-diet. Such a phenomenon is considered to be due to a genetic impairment in the renal excretion of sodium. In the present studies extent of endogenous angiotensin-II (Ang-II) mediated antinatriuresis was comparatively evaluated in Dahl salt-sensitive (SS) and salt-resistant (SR) rats, using a selective AT1 receptor antagonist, candesartan. In addition, differences in plasma renin activity and characteristics of Ang-II receptors in the renal cortical tubular membranes were also examined. Under INACTIN anesthesia AT1 receptor blockade resulted in significant increases in renal sodium excretion, which was several-fold greater in SS rats than that observed in SR rats. These observations suggest that antinatriuretic function of endogenous angiotensin-II is exaggerated in SS rats. This functional overexpression appears to be related to an increase in the affinity of Ang-II receptors in renal cortical tubular membranes but not to receptor density or plasma renin activity. It is proposed that salt-dependent hypertension in Dahl salt-sensitive rats may be due to enhanced Ang-II mediated sodium retention.

Significance of exaggerated natriuresis after angiotensin AT1 receptor blockade or angiotensin- converting enzyme inhibition in obese Zucker rats.

1. Obese Zucker rats (OZR) were shown to be salt-sensitive in that they develop hypertension when placed on a high-salt diet. Because angiotensin (Ang) II is a major antinatriuretic factor, the present studies were undertaken to determine whether the characteristic of salt-sensitivity of OZR is associated with an enhanced antinatriuretic function of endogenous AngII. 2. The extent of AngII-mediated antinatriuresis was investigated in OZR and lean Zucker rats (LZR) using candesartan (100 microg/kg, i.v.), a selective angiotensin AT1 receptor antagonist, and ramipril (1 mg/kg, i.v.), an angiotensin-converting enzyme (ACE) inhibitor. The total number of AngII binding sites and their affinity were also assessed in renal cortical tubular membrane preparations of OZR and LZR using a specific radioligand-binding assay. Plasma renin activity was determined using a standard radioimmunoassay. 3. Both candesartan and ramipril produced substantially greater increases in urinary sodium excretion and urine flow in OZR and these effects were significantly greater than those observed in LZR. These observations suggest that basal antinatriuretic function of endogenous AngII is exaggerated in OZR. 4. The functional overexpression of AngII was not due to any alterations in the affinity or the total number of AngII binding sites in renal cortical tubular membranes. Higher plasma renin values in the OZR could have contributed to the phenomenon. 5. In conclusion, marked diuresis and natriuresis after AT1 receptor blockade and/or ACE inhibition suggest that the extent of endogenous AngII-mediated sodium transport under basal conditions is greatly augmented in OZR. It is proposed this phenomenon may be a contributing factor for the salt- sensitivity in the OZR.

Efficacy and mechanisms of dopexamine in the prevention of ischemia-reperfusion induced organ damage: role of oxygen free radicals.

The studies reported in this article provide evidence that several complex mechanisms are involved in the ability of dopexamine HCl (DPX) in preventing ischemia-reperfusion induced organ damage. In a canine model of hemorrhagic shock in which shed-blood was reinfused, DPX prevented deterioration in renal blood flow via an action on beta-2 and DA-1 receptors, whereas its ability to preserve tubular function was essentially due its agonistic effects on DA-1 receptors. In a different experimental model in anesthetized rats, acute generation of oxygen free radicals (OFR) via intravenous administration of Xanthine (X) followed by Xanthine Oxidase (XO) resulted in depression of circulation and death of more than 80% of the animals within the observation period of 120 min. Pretreatment of the rats with DPX significantly enhanced survival rate in a dose dependent manner to about 70%. Neither dobutamine nor prenalterol, which are beta-1 adrenoceptor agonists and like DPX, potent chronotropic and inotropic agents were effective in preventing OFR induced lethal toxicity. In a separate series, a selective DA-1 receptor agonist felodopam had no protective effect and a DA-1 receptor antagonist SCH-23390 failed to antagonize the salutary effects of DPX. In contrast, salbutamol, a selective beta-2 adrenoceptor agonist significantly promoted the survival rate facilitated by DPX and a selective beta-2 adrenoceptor antagonist, ICI-558,551 significantly attenuated the survival rate. These later studies suggest that unlike in hemorrhagic shock, the beta-2 adrenoceptor agonistic properties are critical in the ability of DPX to attenuate lethal toxicity and these effects could be related to prevention of lipid peroxidation induced by oxygen free radicals.

Evaluation of hemodynamics, vascular reactivity and baroreceptor compensation in the insulin resistant Zucker obese rats.

Incidence of essential hypertension has been reported to be significantly higher in the population afflicted with non-insulin dependent diabetes mellitus (NIDDM). The present studies were under taken in the insulin resistant, Zucker obese rats to evaluate various factors that could lead to the development of high blood pressure. Direct blood pressure measurements in the conscious obese rats indicated that they were not consistently hypertensive although the blood pressures of the obese rats tended to be higher than that of the control lean rats. However, after Inactin anesthesia blood pressures of the obese rats were significantly elevated which can be related to an increase in sympathetic tone since autonomic ganglionic blockade eliminated the differences between the pressures of the two groups. Under anesthesia, cardiac output per 100 gm body weight was significantly lower indicating inadequate tissue perfusion in the obese rats. In a separate series of studies carried out in conscious rats, reflexly mediated alterations in the heart rate to intravenous phenylephrine and sodium nitroprusside were significantly blunted in the obese rats. These observations which include enhanced central sympathetic discharge, inadequate systemic hemodynamics and attenuation of baroreceptor compensation collectively suggest that the insulin resistant obese rats are in a pre-hypertensive state and could develop sustained hypertension if they are exposed to other risk factors.

Effect of pharmacological interventions in the prevention of lipid peroxidation and respiratory depression induced by oxygen free radicals in anesthetized rats.

We have recently reported that in an anesthetized rat model, generation of oxygen free radicals (OFR) via i.v. administration of Xanthine plus Xanthine Oxidase [X + XO] resulted in death of about 90% of the animals within a 120-min observation period. Pretreatment of the rats with endogenous scavengers Superoxide Dismutase and Catalase, or with felodipine, a dihydropyridine calcium channel blocker, and/or with dopexamine, an agonist of beta 2 adrenoceptors as well as dopamine (DA-1) receptors significantly enhanced the survival rate to over 70%. The present study was designed to investigate whether lipid peroxidation and ensuing respiratory depression contributed to the lethal toxicity of the free radicals. In the control group, the death of the rats administered [X + XO] was proceeded by significant increases in the plasma lipid peroxides (PLP) and by a severe hypertensive response characteristic of an intense ischemic state, which was confirmed by the presence of hypercapnia, hypoxemia, and acidosis. Placement of the animals on the positive pressure ventilation prior to the administration of [X + XO] did not prevent increases in PLP but, prevented any adverse alterations in the respiratory markers and significantly enhanced survival rate up to 70%. In contrast, both felodipine as well as dopexamine prevented any increases in PLP, normalized blood gas profile, and significantly increased survival rate to 80 to 90%. These observations suggest that the lethal toxicity produced by oxygen free radical was due to respiratory distress. The relationship between increases in the PLP and respiratory depression and the mechanisms via which two pharmacologically distinct agents, felodipine and dopexamine, facilitated the salutary effects cannot be conclusively stated at this time. It is further suggested that although the doses of these two drugs employed in the present studies are not adequate to function as antioxidants, such a possibility cannot be entirely ruled out.

Age-dependent alterations in Na+, K(+)-ATPase activity in the central nervous system of spontaneously hypertensive rats: relationship to the development of high blood pressure.

We have previously demonstrated that cerebroventricular administrations (i.c.v) of potassium chloride solutions (KCl; 0.375-1.25 mumoles/5 microliters) elicit ouabain-sensitive, concentration-dependent decreases in the blood pressure and heart rates of anesthetized, normotensive Sprague-Dawley (SD) rats. These studies have suggested an inverse relationship between Na(+)-pump activity in the central nervous system (CNS) and central sympathetic outflow. Such a view is further supported by the present studies showing that i.c.v. injections of KCl failed to produce any alterations in the blood pressures of rats pretreated with an autonomic ganglionic blocker, chlorisondamine. In the present studies, depressor responses to i.c.v. potassium chloride were considered as functional indices for evaluation of neuronal Na(+)-pump activity in 8 and 12 week old (8 wk and 12 wk) SHR, WKY and Sprague-Dawley (SD) rats. Basal arterial blood pressures of 8 wk-old SD and SHR, and the responsiveness of these two groups to i.c.v. potassium chloride solutions are similar and they both are significantly greater than that of age matched WKY. However, in the 12 wk-old groups, arterial pressure of SHR was significantly greater than that of WKY as well as SD, whereas the depressor responses to KCl in SHR were significantly greater than that of only WKY. Pretreatment of the rats with i.c.v. ouabain abolished the differences in the hypotensive responses to i.c.v. potassium chloride that existed between various groups but not the differences in the basal blood pressures. Evaluation of these data suggest that a) the centrally mediated hypotensive responses to K+ in various groups could depend upon Na+, K(+)-pump activity in C.N.S. and/or on basal central sympathetic discharge; b) central sympathetic activity is greater in SHR only when compared to WKY but not to SD; c) since the central Na(+)-pump activity and sympathetic tone appears to be similar in SHR and SD, mechanisms other than the increases in sympathetic activity must play a prominent role in the development of spontaneous hypertension; d) attenuation of neuronal Na(+)-pump activity cannot account for greater sympathetic tone in SHR and SD-rats when compared to WKY.

Studies on the pharmacological interventions to prevent oxygen free radical (OFR)-mediated toxicity; effects of dopexamine, a DA1 receptor and beta 2 adrenoceptor agonist.

We have previously demonstrated that the lethal effects of free radicals generated by intravenous administration of Xanthine (X: 0.225 mg kg-1) and Xanthine Oxidase (XO: 5 u kg-1) were prevented by calcium channel blockers such as felodipine (a dihydropyridine calcium antagonist) and verapamil. These studies have implicated that there may be potential interactions between free radicals and cell calcium. However, alternate mechanisms such as hemodynamic changes in the overall effects of calcium antagonists cannot be ruled out. Therefore, the present studies are conducted to further investigate the efficacy of various cardiovascular agents such as Dopexamine (DPX) on [X+XO]-induced mortality. Intravenous administration of [X+XO] to anesthetized rats produced a rapid decrease in blood pressure and a mortality rate of over 90%. Pretreatment with dopexamine, a dopamine receptor (DA1) and beta 2 adrenoceptor agonist significantly enhanced survival upto 70%. Neither dobutamine nor prenalterol, (preferential beta 1 agonists) both of which produced similar increases in heart rate as DPX, enhanced survival rate thus suggesting that cardiac stimulation alone, did not contribute to the protective effects of DPX. Likewise, fenoldopam, a DA1 agonist and a vasodilator also failed to have any significant protective effect on [X+XO]-induced mortality suggesting that the DA1 receptor activation alone cannot account for the salutary effects of dopexamine. Pretreatment of the rats with Salbutamol, a preferential beta 2 agonist significantly enhanced survival upto 50% and a beta 2 antagonist ICI 118,551 significantly attenuated the ability of dopexamine to promote survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative evaluation of the acute effects of oxygen free radicals on myocardial contractility in anesthetized dogs with those occurring in the early stages of splanchnic artery occlusion and hemorrhagic shock.

Oxygen free radicals are cytotoxic and generated in excessive quantities during reoxygenation of ischemic organs. It has been demonstrated that oxygen free radicals impair cardiac contractile mechanisms in in vitro studies as well as depress myocardial contractility in in vivo experiments. The objectives of the present studies are to evaluate alterations in cardiac contractility and hemodynamics in two canine models of shock, namely, Wigger's model of hemorrhage and splanchnic artery occlusion (SAO) model. The data obtained in these models are comparatively evaluated with that caused by oxygen free radicals. Pentobarbital anesthetized dogs were instrumented to record blood pressure, heart rate, left ventricular pressure, (LVP & LVEDP) and LVdp/dt. Contractility index was evaluated as max dp/dt.p. In the Wigger's model, during the period of hemorrhage or after reinfusion of the shed blood despite marked variations in preload and afterload, index of contractility was not altered. Similarly, in the SAO model also, during the period of occlusion or after release, contractility index was not depressed. However, in both the models, after reinfusion of the blood (Wigger's) or after release of splanchnic arteries, there were gradual deteriorations of stroke volume, cardiac output, and arterial blood pressure. In contrast, after generation of free radicals by exogenous administration of xanthine plus xanthine oxidase, cardiac contractility was significantly depressed leading to decreases in stroke volume, cardiac output, and blood pressure. Using identical procedures to evaluate contractility, we have demonstrated that the initial depression of myocardial contractility was not the causative factor for circulatory failure in the two models of shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the effects of dopexamine, a novel DA1 receptor and beta 2-adrenoceptor agonist, on cardiac function and splanchnic circulation in a canine model of hemorrhagic shock.

In the present studies, the efficacy of dopexamine hydrochloride, a novel DA1-receptor and beta 2-adrenoceptor agonist in preventing deterioration of cardiovascular function in a canine model of hemorrhagic shock was investigated. Pentobarbital-anesthetized dogs were allowed to bleed into a height-regulated reservoir and the hypotensive state (about 40 mmHg) was maintained for a period of 150 min. Subsequently, blood was reinfused and recoveries in various hemodynamic variables were monitored for an additional period of 120 min. Either aqueous solvent or dopexamine HCl was randomly selected for i.v. infusion beginning 30 min before reinfusion of the blood and until the termination of the experiment. In the solvent-treated control group, various cardiovascular variables such as cardiac output, stroke volume, celiac and superior mesenteric arterial blood flows progressively declined to 50% or less of the basal values; these changes were associated with sustained increases in the regional as well as systemic vascular resistances. Dopexamine infusion lowered vascular resistances and facilitated recoveries in various hemodynamic variables to 80% to 100% of the basal values after reinfusion of the shed blood. With the exception of a transient inotropic effect during reinfusion in the dopexamine treated group, there were no essential alterations in the myocardial contractility, during the hypotensive state and/or after reinfusion of the blood. Hence, the results indicate that the efficacy of dopexamine to reduce vascular resistance by actions at DA1-receptors and beta 2-adrenoceptors would account for its ability to improve myocardial performance (secondary to reductions in afterload) and restoration of mesenteric and celiac hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological significance of Na+/K(+)-ATPase activity in the central nervous system and endogenous sodium-pump inhibitors in the neural regulation of arterial blood pressure.

In anesthetized Sprague-Dawley rats, cerebrolateral ventricular administration of potassium chloride solutions (KCl, 0.375-1.25 mumol, i.c.v.) produced concentration-dependent reductions in the arterial blood pressure and heart rate. These responses were significantly attenuated by prior i.c.v.-administration ouabain, a selective inhibitor of the Na+ pump, and by endothelin (ET-1), an endogenous peptide that is present in the CNS, suggesting that this peptide may participate in the neural regulation of arterial pressure via modulation of Na(+)-pump activity. Although both acute fluid volume expansion and/or osmotic stimulus have been shown to facilitate the release of the endogenous Na(+)-pump inhibitor(s) into the circulation, only volume expansion significantly attenuated the cardiovascular effects of i.c.v. potassium chloride. These observations collectively suggest that the Na+, K(+)-ATPase activity in CNS and Na(+)-pump inhibitors may play a significant role in the central regulation of arterial pressure under certain physiological conditions.

Evaluation of the effects of felodipine, verapamil and hydralazine on the survival rate of rats subjected to lethal effects of oxygen free radicals.

Intravenous administration of xanthine (X: 0.225 mg/kg, i.v.) plus xanthine oxidase (XO: 3.0 units/kg, i.v.) to anesthetized rats resulted in a rapid fall in the arterial pressure and a mortality rate of over 80% during 120 min observation period. Pretreatment of the rats with superoxide dismutase (SOD) or SOD plus catalase significantly enhanced survival rate to 60% confirming that the toxicity after [X + XO] administration is due to the generation of oxygen free radicals. Pretreatment of the rats with either felodipine, a dihydropyridine calcium antagonist or verapamil, a structurally different Ca(2+)-channel blocker was most effective in promoting survival rate to 90%; in contrast, hydralazine, an arteriolar dilator but not a calcium antagonist, was ineffective in significantly enhancing survival. In the vehicle treated groups, mortality of the rats after [X + XO] administration was associated with significant increases in serum creatine phosphokinase (CPK) levels; both the calcium antagonists as well as hydralazine prevented any significant changes in CPK levels. Since only the calcium antagonists but not hydralazine were effective in providing significant protection against mortality, the data suggests that CPK may not be a reliable indicator to predict prevention of lethal toxicity induced by free radicals. Hence, the observation that calcium antagonists can promote survival would suggest that calcium overload may be the ultimate mediator of tissue toxicity. These observations can account for the remarkable efficacy of various calcium antagonists in preventing ischemia-reperfusion induced damage to organs, such as heart and kidneys, in which a role for free radicals has been postulated.

Evaluation of the efficacy of felodipine in two models of acute renal failure in dogs.

Acute renal failure was induced in pentobarbital anesthetized dogs either by withdrawal of the blood and/or by acute renal artery occlusion and efficacy of felodipine in preserving renal function was evaluated. In Wiggers' model of hemorrhagic shock, animals were allowed to bleed into a reservoir and after maintaining a hypotensive state (40-45 mm Hg) for 150 minutes, blood was reinfused and recovery in the renal function was evaluated. In a separate series, a renal artery was completely occluded for 45 minutes and after release of the occlusion recoveries in various markers of renal function were monitored. Felodipine 0.01 mumol/kg i.v. or the vehicle was administered ten minutes before hemorrhage or ten minutes prior to initiation of renal artery occlusion. Comparison of the data between the vehicle-treated dogs from the two models show that although renal blood flow (RBF) was restored to similar levels, recoveries in glomerular filtration rate (GFR), urine volume (UV), urinary excretion of sodium (UNa V) and potassium (UK V) were severely depressed in shock model (15 to 25% of the basal value) and consistently lower than the recoveries in the renal artery occlusion model (30-50%). These data could suggest that the extent of renal impairment is more severe in hemorrhagic shock. Nevertheless, felodipine pretreatment provided significant protection to renal function from ischemic damage in both the models; the drug-treated groups were characterized by significant recoveries in GFR, UNa V and UK V (60-100%) and by prompt and full restoration of RBF and UV.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism by endothelin of centrally mediated cardiovascular effects of potassium in anaesthetized rats.

1. We have previously demonstrated that cerebroventricular administration of potassium chloride (KCl) solutions produces dose-dependent reductions in blood pressure and heart rate in anaesthetized rats and that these effects are significantly attenuated by ouabain, a selective inhibitor of the Na(+)-pump. These observations suggest an important relationship between Na+,K(+)-ATPase activity in the central nervous system (CNS) and neural mechanisms involved in the regulation of cardiovascular function. 2. Since endothelin-1 (ET-1) has been shown to affect various ion transport mechanisms, including the Na(+)-pump, the present studies were conducted to evaluate whether this peptide would antagonize central effects of KCl. 3. The present studies demonstrate that cumulative doses of ET-1 (0.8-3.2 pmol, intracerebrolateral ventricular administration, i.c.v.) produced significant attenuation of hypotension and bradycardia produced by i.c.v. injections of KCl (0.75 mumol/5 microL, i.c.v.); in a separate series, a single high dose of ET-1 (4.0 pmol, i.c.v.) significantly reduced cardiovascular responses to various doses of KCl (0.375, 0.75, 1.25 mumol/5 microL, i.c.v.). 4. These studies suggest that endothelin may be involved in the regulation of arterial pressure since it is present in CNS and possesses a ouabain-like effect. However, it is not conclusive that ET-1 inhibits neuronal Na(+)-pump, since alternative mechanisms can also account for the efficacy of the peptide to antagonize central effects of potassium chloride.

Role of Na+,K(+)-ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats.

Several investigators have demonstrated the antihypertensive properties of potassium in various models of hypertension. The present studies were conducted to determine whether central mechanisms contribute to these salutary effects of potassium. In Inactin-anaesthetized rats, intracerebroventricular administration of KCl solutions (0.375, 0.75 and 1.25 mumol/5 microliters) produced concentration-dependent reductions in arterial pressure and heart rate. These effects were significantly attenuated by prior central administration of ouabain, a selective inhibitor of the sodium pump. In a separate series of experiments, prior central administration of alpha 1- and alpha 2-antagonist phentolamine, or the dopamine receptor (DA1 and DA2) antagonist RS-sulpiride, was also effective in inhibiting the hypotensive and bradycardiac effects of intracerebroventricular administration of potassium. Thus, these data suggest that activation of Na+,K(+)-ATPase and central noradrenergic and dopaminergic mechanisms are involved in the central actions of potassium and these central mechanisms may contribute to the salutary effects of a potassium-rich diet in hypertensive subjects. The present studies demonstrate a potentially important relationship between Na+,K(+)-ATPase activity in the central nervous system and neural regulation of arterial blood pressure.

Studies on the role(s) of cerebrospinal fluid osmolality and chloride ion in the centrally mediated pressor responses of sodium chloride.

These studies were designed to investigate whether the centrally mediated pressor effects of hypertonic sodium chloride (NaCl) solutions are triggered in response to changes in the cerebrospinal fluid (CSF) osmolality and whether the chloride ion plays a role in these effects. In Inactin anesthetized, vagotomized rats, alterations in the arterial pressure to cerebroventricular administration (i.c.v.) of various concentrations of NaCl, sodium nitrate (NaNO3), glycerol, creatinine, lithium chloride (LiCl), lithium nitrate (LiNO3) and choline chloride were evaluated. The pressor effects of NaCl were significantly greater than those produced by either glycerol, creatinine and/or NaNO3 solutions. Central effects of NaCl were identical to that of LiCl; likewise, NaNO3 and LiNO3 produced essentially similar increases in the blood pressure. In other words, the two chloride salts produced significantly greater increases in the arterial pressure than the nitrate salts. Choline chloride also produced significant increases in the blood pressure both before and after pretreatment with hemicholinum (i.c.v.). In a separate series of experiments, pretreatment of rats with a vasopressin antagonist (i.v.), significantly attenuated the pressor effects of NaCl, NaNO3 and that of choline chloride whereas after autonomic ganglionic blockade with chlorisondamine, pressor responses of only NaCl, but not those of NaNO3 or choline chloride were significantly inhibited. These data indicate that elevation of either Na+ or Cl- in the CSF facilitates vasopressin secretion and that Na+ and Cl- ions function synergistically in the central nervous system (C.N.S.) to enhance sympathetic activity. The present studies demonstrate that the circumventricular structures in the C.N.S. that participate in the regulation of blood pressure are more responsive to changes in concentrations of Na+ and Cl- rather than to net changes in the CSF osmolality. The data further suggest that the chloride ion contributes to the central pressor effects of NaCl and may play a role in the pathophysiology of salt-dependent hypertension.

Comparative evaluation of the effects of felodipine, hydralazine, and naloxone on the survival rate in rats subjected to a "fixed volume" model of hemorrhagic shock.

Felodipine, a dihydropyridine calcium antagonist with potent arteriolar dilator properties, has been shown to enhance renal, mesenteric, coronary, and cerebral blood flows in intact animals as well as in man and to prevent deterioration of renal and mesenteric blood flows in Wiggers' model of hemorrhagic shock in dogs. In the present studies, efficacy of felodipine on 72 hr survival of rats subjected to an acute withdrawal of 40% of the blood volume was investigated. Shed blood was not reinfused in the present studies. Felodipine, whether administered before or after hemorrhage, facilitated dose-dependent increases in the survival rate up to 95%, whereas in the vehicle-treated group, the survival rate was 33%. Hydralazine, also an arteriolar dilator, in equi-hypotensive doses was not as effective as the calcium antagonist. Effects of felodipine are comparable to that of naloxone in enhancing survival. These data suggest that the salutary effects of felodipine can be related to its calcium antagonistic as well as arteriolar dilator properties.

Antidiuretic effects of neurotensin in chloralose anaesthetized dogs.

1. Effects of cerebroventricular and/or intravenous infusions of neurotensin (NT), an endogenous tridecapeptide, on haemodynamics and renal function were investigated in chloralose anaesthetized dogs. 2. Cerebroventricular infusions (i.c.v.) of NT (10-6 mol/L and 10-5 mol/L, 0.1 mL/min) for 30 min did not produce any significant alterations in the measured variables. In the vagotomized dogs, intravenous (i.v.) infusion of NT (10(-5) mol/L) at a rate of 0.1 mL/min for 30 min significantly lowered the arterial blood pressure and glomerular filtration rate; these effects were accompanied by pronounced reductions in the urine flow and urinary sodium excretion and marked increases in urine osmolality. 3. In the dogs with vagi intact, i.v. infusions of NT failed to produce any alterations in the blood pressure; however, renal effects of NT were essentially identical to those observed in the vagotomized dogs. 4. Infusions of NT (10(-6) mol/L) and/or NT-metabolites NT1-8 and NT8-13 (10(-5) mol/L) directly into the renal artery failed to produce any significant alterations in the urine flow. Antidiuretic effects of i.v. NT were not prevented by acute renal denervation, adrenalectomy, or pretreatment of the animals with naloxone. However, morphine pretreatment completely abolished the hypotensive and anti-diuretic effects of NT. 5. It is proposed that i.v. infusion of NT rapidly facilitates the secretion of an endogenous substance possessing potent antidiuretic properties and opiate mechanisms are involved in mediating such an effect. Although it appears unlikely, a role for vasopressin cannot be ruled out.

Renal failure in haemorrhagic shock in dogs: salutary effects of the calcium entry blocker felodipine.

The efficacy of felodipine, a dihydropyridine calcium entry blocker to restore renal function was investigated in Wiggers model of haemorrhagic shock. Mongrel dogs were anaesthetized with sodium pentobarbital and subjected to haemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure 40-45 mm Hg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) Solvent control, (B) Felodipine 0.01 mumol/kg i.v., administered 10 min prior to reinfusion of the blood, and (C) Felodipine 0.01 mumol/kg i.v., administered prior to haemorrhage. In all the three groups arterial blood pressure returned to similar basal levels following reinfusion. Felodipine administration prior to haemorrhage or before reinfusion (Group B and C) resulted in a 80-95% recovery in the renal blood flow, 60-65% in the glomerular filtration rate, 150-300% in the urine volume and 80-100% in the urinary sodium and potassium excretions. In the vehicle-treated control group, despite a 45% recovery in the renal blood flow, renal function was not restored following reinfusion. The observations made in these studies suggest that felodipine, an arteriolar dilator which also possesses natriuretic properties, could be clinically useful in the treatment of renal failure in haemorrhagic shock. Prevention of cellular calcium overload during ischaemia and reperfusion by this dihydropyridine derivative, may account for its ability to preserve vascular as well as tubular function.