Myocardial vasoactive intestinal peptide and fibrosis induced by nitric oxide synthase inhibition in the rat.

AIMS: In both normotensive and hypertensive rats, the degree of myocardial fibrosis is inversely correlated with the concentration of vasoactive intestinal peptide (VIP) in the myocardium. Treatment with nitric oxide (NO) synthase inhibitors also causes myocardial fibrosis. In this study, we sought to determine whether the myocardial fibrosis induced by treatment with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) was also associated with depletion of VIP in the myocardium. METHODS: Male Wistar Kyoto (WKY) and spontaneous hypertensive rats (SHR) rats treated with l-NAME were randomized to low, intermediate or high salt content diets. After 4 weeks, the hearts were harvested, the degree of fibrosis quantified and VIP concentration measured. RESULTS: In WKY, systolic blood pressure increased with increasing dietary sodium (P < 0.05). Myocardial fibrosis also increased with increasing dietary sodium (P < 0.005). Myocardial VIP concentration decreased with increasing dietary sodium (P < 0.025). In contrast, in the SHR treated with l-NAME, systolic blood pressure increased but the increase was not affected by sodium intake. Further, myocardial fibrosis and myocardial VIP were unchanged by increased dietary sodium. Higher doses of l-NAME in the SHR did not increase the systolic blood pressure, increase the degree of myocardial fibrosis or decrease the myocardial concentration of VIP. These differences in myocardial VIP concentration may reflect differing effects of l-NAME on VIP metabolism, as l-NAME increased VIP metabolism in the WKY (P < 0.05) but did not change VIP metabolism in the SHR. CONCLUSIONS: We conclude that depletion of VIP in the myocardium is associated with increasing myocardial fibrosis in l-NAME treated WKY. As VIP depletion occurs in other models of myocardial fibrosis, it appears to be a common mechanism. Myocardial VIP depletion may therefore be a new and important factor in the pathogenesis of cardiac fibrosis.

Dysregulation of angiotensin II synthesis is associated with salt sensitivity in the spontaneous hypertensive rat.

(1) Salt sensitive hypertension, which occurs as a result of treatment with nitric oxide synthase inhibitors, is associated with a loss of the usual down-regulatory effect of dietary sodium on angiotensin II (Ang II) synthesis. In the spontaneous hypertensive rat (SHR), which suffers a relative NO deficiency, the hypertension is in part salt sensitive. We sought to determine therefore whether the salt sensitive component to the hypertension was associated with a loss of the regulatory effect of dietary sodium on Ang II synthesis. (2) Male SHR were placed on low, intermediate or high salt diets for 4 weeks and their blood pressure recorded. After 4 weeks, blood was collected for determination of renin, angiotensinogen, Ang I, Ang II and aldosterone concentrations, as well as ACE activity. (3) The increase in systolic blood pressure in rats on the high salt diet was significantly greater than in those on the low (P < 0.005) and intermediate salt diets (P < 0.0005). Plasma renin and aldosterone concentrations and ACE activity decreased with increasing dietary sodium. However, the concentrations of Ang II and angiotensinogen both increased in the rats on the high salt diet (Ang II: P < 0.05; angiotensinogen: P < 0.05). (4) We conclude that the hypertension in the SHR is in part salt sensitive and that this salt sensitive component is associated with a loss of the normal down-regulatory effect of dietary sodium on Ang II and angiotensinogen synthesis.

Salt-sensitive hypertension resulting from nitric oxide synthase inhibition is associated with loss of regulation of angiotensin II in the rat.

In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008 %, 2.2 % or 4.4 % sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg(-1) day(-1)) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist.

Factors regulating renal angiotensin-converting enzyme activity in the rat.

Changes in angiotensin-converting enzyme (ACE) activity appear to be important in mediating the natriuresis which ensues after administration of an oral or gastric sodium load. In this study, we sought to determine the time course of the changes in ACE activity in the kidney which occur after sodium ingestion. In addition, we sought to investigate mechanisms which might underlie these changes. Angiotensin-converting enzyme activity was measured by generation of histidyl-leucine in homogenates of kidneys harvested at varying time-points after gastric sodium administration. The effects of intravenous sodium loading, solution osmolality and of changes in renal nerve activity were also investigated. Intragastric instillation of both the sodium-containing solution and its iso-osmotic urea control solution resulted in significant increases in renal ACE activity (NaCl: P < 0.0005; Urea: P < 0.01). The increase in renal ACE activity after gastric sodium loading was more prolonged than after the urea control (P < 0.025, NaCl vs. urea at 90 min). This prolonged increase in renal ACE activity appeared to reflect a response to absorbed sodium as intravenous sodium administration caused a significant increase in renal ACE activity at 90 min (P < 0.0005). In contrast to these stimuli which increased renal ACE activity, renal denervation caused a significant decrease in ACE activity in the kidney (P < 0.05). We conclude that gastric sodium loading increases renal ACE activity. This effect appears to be due initially to a response to an increase in gastric lumenal osmolality and later to absorbed sodium. These changes in renal ACE activity are not mediated by a decrease in renal nerve activity.

Vasoactive intestinal peptide down-regulates the intrahepatic renin-angiotensin system in the anaesthetized rat.

Gastric sodium loading results in an increase in the portal venous concentration of vasoactive intestinal peptide (VIP) and down-regulation of both the intrahepatic and circulating renin-angiotensin systems. In the present study we sought to determine whether an increase in the concentration of VIP in the portal circulation might act to down-regulate the intrahepatic and/or circulating renin-angiotensin systems. Male Sprague-Dawley rats were infused intraportally with haemaccel vehicle or VIP in haemaccel for 60 min. Livers were harvested and blood was sampled. Angiotensin-converting enzyme (ACE) activity and angiotensinogen, angiotensin I, angiotensin II and renin concentrations were measured. VIP infusion decreased hepatic ACE activity (P < 0.05), the hepatic angiotensinogen concentration (P < 0.001) and the hepatic angiotensin I concentration (P < 0.05). The plasma angiotensinogen concentration and serum ACE activity were also decreased by intraportal VIP infusion (P < 0.05 for each). Plasma renin, angiotensin I and angiotensin II concentrations were unchanged by VIP infusion. We conclude that an increase in the portal venous VIP concentration down-regulates the intrahepatic renin-angiotensin system. These changes are similar to those reported after gastric sodium loading, and we suggest, therefore, that the increase in portal venous VIP that occurs after gastric sodium is the means by which the gastric sodium sensor signals the liver to effect these changes in the renin-angiotensin system.

Modulation of the intrahepatic renin-angiotensin system after stimulation of the gastric sodium monitor in the rat.

Changes in the rate of formation of angiotensin II (ANG II) participate in mediating the natriuresis that occurs in direct response to a gastric sodium stimulus (upper-gut sodium monitor). As this natriuresis is also dependent on intrahepatic events, we investigated whether changes in hepatic and plasma angiotensinogen levels and hepatic angiotensin-converting enzyme (ACE) activity might explain the decrease in ANG II synthesis. Male Sprague-Dawley rats, equilibrated on a low-sodium diet, were anaesthetized and received a sodium load of 1.5 mmol/kg (using 3 x normal saline) either intragastrically or intravenously. Blood and livers were sampled before and at various times after sodium administration. ACE activity in serum and tissues was determined by generation of histidyl-leucine. Angiotensinogen was determined by radioimmunoassay of angiotensin I generated by incubation in the presence of exogenous renin. Plasma angiotensinogen had decreased significantly by 15 min after sodium administration (P<0.005), while hepatic angiotensinogen was also decreased significantly from 30 min after the sodium load (P<0.01). Hepatic ACE activity decreased in response to sodium (P<0.005) from 30 min. We conclude that stimulation of the gastric sodium monitor regulates angiotensinogen synthesis and secretion by the liver, as well as hepatic ACE activity.

Effects of enalapril on vasoactive intestinal peptide metabolism and tissue levels.

Angiotensin converting enzyme inhibitor therapy results in an increase in cardiac output without an increase in heart rate suggesting a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations. Angiotensin converting enzyme may also metabolise vasoactive intestinal peptide (VIP), a vasodilator and positive inotrope whose concentration in the heart declines in heart failure. We sought to determine whether changes in plasma VIP or its metabolism might explain the positive inotropic effect of angiotensin converting enzyme inhibitors. We also measured VIP in the heart to determine whether a local increase in VIP might explain this effect. Male Sprague-Dawley rats were randomised to control and enalapril groups (2 mg kg(-1) day(-1)). After 7 days, rats were anaesthetised and underwent metabolic clearance studies for VIP or had hearts, lungs and kidneys removed and snap frozen. VIP concentrations in plasma, infusate and tissue extracts were measured by radioimmunoassay. Plasma concentrations of VIP were unchanged by treatment with enalapril (control: 7.7 +/- 0.8 pmol l(-1); enalapril: 7.9 +/- 0.8 pmol l(-1) ), while the metabolic clearance rate of) VIP increased significantly (control: 10.4 +/- 1.4 ml min(-1) 100 g(-1); enalapril: 17.3 +/- 1.6 ml min(-1) 100 g(-1); p < 0.005). Secretion rate) also increased in enalapril treated rats (139.1 +/- 25.0 pmol min(-1) 100 g(-1) compared with controls (96.3 +/- 13.4 pmol min (-1) 100 g(-1); P< 0.01). VIP in the heart increased after enalapril (control: 208.4 +/- 39.0 pmol g (-1); enalapril: 928.9 +/- 123.6 fmol g(-1); P < 0.0005). Angiotensin converting enzyme inhibition increases the metabolism of VIP. However, the significant increase in the myocardial concentration of VIP may contribute to the beneficial haemodynamic inotrope effects of angiotensin converting enzyme inhibitors.

Mechanisms underlying the decrease in circulating angiotensin II concentration after sodium loading.

1. Acute sodium loading causes a rapid decrease in the circulating concentration of angiotensin II (AngII), which is apparent from 5 min after sodium administration. This could result from an increase in AngII catabolism and/or a decrease in AngII synthesis/secretion. However, the major determinant of AngII synthesis is thought to be a change in plasma renin activity, which occurs over a longer time frame (15 min). 2. To investigate the mechanisms underlying the rapid decrease in plasma AngII engendered by sodium administration, we performed metabolic clearance studies in male New Zealand white rabbits before and after a hypertonic sodium load of 1.5 mmol/kg as 0.513 mol/L saline i.v. bolus. 3. The metabolic clearance rate of AngII increased significantly from 42.2 +/- 9.0 mL/min per kg before sodium to 110.8 +/- 33.7 mL/min per kg after sodium administration (P < 0.05). The calculated or theoretical secretion rate decreased from 1470.7 +/- 404.2 to 573.5 +/- 139.5 fmol/min per kg (P < 0.025) in response to sodium. 4. We conclude that an increase in AngII metabolism and a decrease in synthesis/secretion contribute to the reduction in circulating AngII, which occurs in the first 60-90 min after sodium loading.

Stimulation of the gastric sodium monitor reduces hepatic angiotensin-converting enzyme activity.

1. The natriuresis engendered by stimulation of the gastric sodium monitor is mediated in part by a decrease in the circulating concentration of angiotensin II (AngII). This decrease is due to decrease in synthesis rather than to an increase in metabolism. We investigated the role of changes in plasma and hepatic angiotensin-converting enzyme (ACE) activity in this decrease in AngII synthesis. 2. Male Sprague-Dawley rats were equilibrated on a low-sodium diet for 7 days. On the day of experiment, rats were anaesthetized and received either a sodium load of 1.5 mmol/kg as 3 mol/L saline or an equivalent volume of an iso-osmotic urea solution by direct gastric puncture. Blood was sampled and livers were harvested at 0 and 30 min after sodium or urea administration. Angiotensin-converting enzyme was measured in serum and tissue homogenates by generation of histidyl-leucine. 3. In the liver, ACE activity decreased from control after both sodium (P < 0.005) and urea (P < 0.025) administration. The decrease was greater in the group that received saline compared with rats that received urea (P < 0.05). Serum ACE decreased in response to urea (P < 0.025) but not sodium administration. 4. We conclude that stimulation of the gastric sodium monitor results in a decrease in ACE activity in the liver. This decrease in ACE activity may be contributory to the decrease in AngII synthesis.

Stimulation of gastric osmoreceptors but not the sodium monitor increases renal angiotensin-converting enzyme activity.

1. Stimulation of the gastric sodium monitor has been reported to cause a decrease in renal nerve activity and also a decrease in plasma renin activity in renal venous blood. This suggests that changes in sympathetic nerve activity and in the intrarenal renin-angiotensin system may mediate the natriuresis that occurs following gastric sodium administration. In the present study we sought to determine whether gastric sodium administration also modulates angiotensin-converting enzyme (ACE) activity in the kidney. 2. Male Sprague-Dawley rats were equilibrated on a low-sodium (0.008%) diet for 7 days. On the day of the experiment, rats were anaesthetized and kidneys were harvested and immediately snap frozen at 0 and 60 min after intragastric administration of a saline load (1.5 mmol/kg as 3 mol/L saline) or an equivalent volume of iso-osmotic urea (5.95%). Angiotensin-converting enzyme activity was determined by incubation of kidney homogenates with hippuryl-histidyl-leucine and fluorometric assay of the histidyl-leucine generated. 3. Angiotensin-converting enzyme activity in the kidney increased in response to the intragastric administration of both sodium chloride and urea. Angiotensin-converting enzyme activity increased significantly from control levels (189.9 +/- 24.3 nmol/min per g protein) by 60 min in both NaCl-and urea-treated groups (492.3 +/- 27.3 and 468.6 +/- 28.7 nmol/min per g protein, respectively; P < 0.0005). 4. We conclude that instillation of sodium chloride or isoosmotic urea into the stomach increase ACE activity in the kidney. The results of the present study suggest that this effect is due to changes in osmolality rather than stimulation of the gastric sodium monitor.

Angiotensin-converting enzyme inhibition with enalapril increases the cardiac concentration of vasoactive intestinal peptide.

In patients with congestive cardiac failure, treatment with ACE inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by the changes in angiotensin II and bradykinin concentrations that occur. It has been suggested that ACE also metabolizes VIP, which is a positive inotrope. As VIP is synthetized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP. Male Sprague-Dawley rats received enalapril (2 mg/kg/day) in the drinking water or no therapy for seven days. On day seven they were anaesthetized and blood sampled. The hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay. Plasma and renal concentrations of VIP did not change in the enalapril-treated rats. However, the myocardial concentration of VIP increased significantly in the rats receiving enalapril compared with control animals (p < 0.0005). We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.

Increases in the myocardial concentration of vasoactive intestinal peptide may explain the positive inotropic effect of angiotensin converting enzyme inhibitors.

1. In patients with congestive cardiac failure, treatment with angiotensin converting enzyme (ACE) inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations that occur. ACE has been suggested to also metabolise vasoactive intestinal peptide (VIP), which is a positive inotrope. As VIP is synthesized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP. 2. Male Sprague-Dawley rats received enalapril (2 mg/kg per day) in their drinking water or no therapy for 7 days. On day 7 the rats were anaesthetized and blood was sampled. Hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay. 3. Plasma and renal concentrations of VIP did not change in enalapril-treated rats. However, the myocardial concentration of VIP increased significantly in rats receiving enalapril compared with control animals (P < 0.0005). 4. We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.

Angiotensin II: a humoral mediator for the gastric sodium monitor.

Natriuresis in direct response to a gastric sodium stimulus (upper-gut sodium monitor) has paradoxically only been demonstrated in humans and animals on a low-sodium diet preceding each study. It is possible that the low-sodium diet itself induces or suppresses systems that mediate or oppose the ensuing natriuresis. In this study, we sought to determine whether a system activated by this diet, the renin-angiotensin system, mediates the natriuretic response. Specifically, we sought to show whether changes in the circulating concentration of angiotensin II (ANG II) may mediate the renal response to stimulation of the gastric sodium monitor. Male New Zealand White rabbits were randomly assigned to low- (0.008%) or normal (2.2%) sodium diets. After 1 wk on the experimental diet, they received a sodium load intragastrically or intravenously, and plasma ANG II was measured at 0, 5, 10, 30, 60, and 120 min. Urine was collected for 4 h after the sodium load, and plasma sodium was measured at 0, 2, and 4 h. Urinary sodium excretion was greater in the 4 h after gastric than after intravenous sodium administration (P < 0.025) in the rabbits on the low-sodium diet. No significant difference was noted in the rabbits on the normal sodium. In rabbits on the low-sodium diet, there was an immediate and significant decline in plasma ANG II after sodium was administered both intragastrically (P < 0.025) and intravenously (P < 0.05). This decrease was greater after intragastric than intravenous sodium (P < 0.0025), and the difference was still evident at 120 min (P < 0.05). No significant difference in plasma ANG II was found in the normal diet group. We conclude, therefore, that a prolonged decrease in ANG II concentration may play a role in mediating the natriuretic response to the gastric sodium monitor.

Effects of endopeptidase 24.11 inhibition on plasma and tissue concentrations of vasoactive intestinal peptide.

1. In this study, we sought to determine the effect of endopeptidase 24.11 inhibition on the rate of metabolism of vasoactive intestinal peptide. The effect of such inhibition on the concentration of vasoactive intestinal peptide in two tissues was also investigated. 2. Male Sprague-Dawley rats were given the endopeptidase 24.11 blocker UK77,568 (10 mg/kg) or vehicle as a single intravenous injection or as a daily injection for 4 days. Two hours after the final or single injection, the rats were anaesthetized and blood was sampled to determine plasma concentrations of vasoactive intestinal peptide and angiotensin II. The hearts and kidneys were harvested and snap-frozen in liquid nitrogen. The plasma and tissue concentrations of vasoactive intestinal peptide and the plasma concentration of angiotensin II were determined by radioimmunoassay. In a separate group of experiments, male Sprague-Dawley rats were anaesthetized and carotid and jugular catheters were inserted. One hour after intravenous administration of UK77,568 or vehicle, an infusion of vasoactive intestinal peptide (10 pmol min-1 kg-1) was commenced via the jugular catheter. Blood was sampled to determine the vasoactive intestinal peptide concentration 1 h after commencing the vasoactive intestinal peptide infusion to calculate the metabolic clearance rate. 3. Plasma vasoactive intestinal peptide increased after acute (P < 0.05) but not chronic administration of UK77,568, while the concentration of vasoactive intestinal peptide in the heart increased after chronic administration (P < 0.0005). The concentration of vasoactive intestinal peptide in the kidney was unchanged after both acute and chronic endopeptidase 24.11 blockade. Plasma angiotensin II decreased significantly in the chronic group (P<0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of dietary sodium on the concentrations of vasoactive intestinal peptide in plasma and lung.

STUDY OBJECTIVES: In this study, we sought to determine whether changes in the concentration of vasoactive intestinal peptide (VIP) in the lung might explain the increase in bronchial reactivity associated with high sodium diets. DESIGN: Male Sprague-Dawley rats, eight in each group, were placed on low-sodium, normal-sodium, or high-sodium diets and distilled drinking water ad libitum for 7 days. On the day of study, blood was sampled to determine plasma VIP concentration and the lungs were harvested and snap frozen in liquid nitrogen. VIP was measured in plasma and tissue extracts by radioimmunoassay. RESULTS: The VIP concentrations in both lung and plasma varied with dietary sodium. Plasma VIP level was significantly higher in the rats that had received the low-sodium diet (51.45 +/- 7.35 pmol L-1) than in the rats that had received the high-sodium diet (29.84 +/- 6.83; p < 0.05). In the lung, VIP level was greater in the rats that had received the normal-sodium diet (378.13 +/- 41.68 fmol/g) than in rats that had received either the low-sodium diet (137.30 +/- 26.11 fmol/g; p < 0.0005) or the high-sodium diet (182.64 +/- 28.63 fmol/g; p < 0.005). CONCLUSIONS: The lower plasma and pulmonary concentrations of VIP observed in rats that had received a high-sodium diet suggest that VIP may play a role in the increased bronchial reactivity reported with this diet.

Effects of sodium depletion on tissue concentrations of the natriuretic hormone vasoactive intestinal peptide.

1. Variations in dietary sodium intake have been shown to affect the plasma concentration, the metabolic clearance rate and secretion rate of vasoactive intestinal peptide (VIP). In this study we sought to determine the effect of sodium depletion on the concentration of VIP in plasma and in three tissues, namely heart, lung and kidney. 2. Male Sprague-Dawley rats were placed on low or normal sodium diets and drinking water ad libitum. A third group was placed on a low salt diet and in addition were given frusemide, 1mg/kg per day in the drinking water. After 7 days the rats were killed, a blood sample collected and tissues harvested. VIP concentrations were determined by radioimmunoassay on unextracted plasma and in tissue after extraction. 3. There were significant differences between the three groups in the concentration of VIP in the lung (P < 0.0005), kidney (P < 0.005) and plasma (P < 0.025) but not the heart. In the group that received frusemide and the low sodium diet, VIP in the lung was significantly lower than the low sodium (P < 0.005) and normal sodium (P < 0.0001) groups. Similar differences were noted in the kidney (frusemide vs low sodium, P < 0.001; frusemide vs normal, P < 0.01) and plasma (frusemide vs low sodium P < 0.001, frusemide vs normal P < 0.05). 4. We conclude that sodium depletion decreases the concentration of VIP in plasma and in its metabolizing tissues.

Vasoactive intestinal peptide regulates angiotensin II catabolism in the rabbit.

Although vasoactive intestinal peptide (VIP) is natriuretic it stimulates renin and aldosterone secretion. Therefore, to effect a natriuresis, VIP may need to modulate the sodium conserving actions of the renin angiotensin system (RAS) by another means. One possibility is that it alters the rate of disappearance from the circulation of one or more components of the RAS. We sought to determine whether VIP regulates the rate of catabolism of angiotensin II (Ang II). Steady state metabolic clearance studies of Ang II were undertaken with and without simultaneous VIP infusion. These studies were performed in rabbits on low, normal and high sodium diets, as dietary sodium has been shown to affect the metabolism of both VIP and Ang II. The effects of VIP on plasma Ang II concentration and secretion were also studied. VIP decreased Ang II catabolism in rabbits on low (P < 0.05) and normal sodium diets (P < 0.05). Plasma levels of Ang II increased significantly in response to VIP in rabbits on these diets (low, P < 0.04; normal, P < 0.05). In contrast, in rabbits on a high sodium diet VIP increased the rate of catabolism of Ang II (P < 0.001). Thus we conclude that the effect of VIP on sodium excretion may be modulated by its effects on Ang II metabolism. The decrease in Ang II catabolism seen in rabbits on low and normal sodium diets may prevent or ameliorate any natriuresis while the more rapid degradation of Ang II which occurs in dietary sodium excess may enhance the natriuretic effect of VIP.

Lidocaine shows greater selective depression of depolarized and acidotic myocardium than propafenone: possible implications for proarrhythmia.

We have previously shown reduced selectivity for depolarized and acidotic myocardium for encainide and flecainide compared to lidocaine and amiodarone. The present study aims to compare propafenone and two of its metabolites (5-OH-propafenone and N-despropyl-propafenone) to lidocaine in the same model. Standard microelectrode methods were used to record intracellular action potentials from strips of guinea pig right ventricular myocardium superfused with either standard physiological saline (pH 7.3; pO2 > 600 mm Hg; [K+] = 5.6 mM), or the same solution modified to produce either hyperkalemia (K+ = 11.2 mM), acidosis (pH = 6.3), or hypoxia (pO2 = 60 mm Hg). The effects on action potential parameters of three "therapeutic" concentrations of lidocaine, propafenone, and two of its metabolites were studied under all four conditions at four different drive rates from 200 to 25 beats/min. Hyperkalemia, in the absence of drugs, produced reductions in the resting potential (-86.7 +/- 2.5 to -71.8 +/- 3.7 mV) and the maximum rate of depolarization (Vmax, 300.0 +/- 46.5 to 205.6 +/- 37.6 V/s). All four drugs produced increased depression of Vmax in hyperkalemia and acidosis compared to control conditions, but it was a consistent finding that at concentrations that were approximately equipotent in control conditions, lidocaine produced greater increments in depression of Vmax in hyperkalemic and acidotic superfusate than did propafenone or either of its metabolites. Qualitatively similar results were obtained for both metabolites compared to lidocaine. Hypoxia produced no significant modulation of drug effects.(ABSTRACT TRUNCATED AT 250 WORDS)