Renal versus hindquarter hemodynamic responses to vasopressin in conscious rats.

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.     

Renal arteriolar contractile responses to angiotensin II in rats with poorly controlled diabetes mellitus

1. Experiments were performed to test the hypothesis that renal arteriolar responses to angiotensin (Ang)II are altered in insulin-dependent diabetes mellitus. 2. Male Sprague-Dawley rats were treated with streptozotocin (STZ; 65 mg/kg, i.v.) or 0.9% NaCl vehicle (Sham). Partial insulin replacement maintained blood glucose levels at 422 +/- 6 mg/dL (STZ rats) for the ensuing 2 week period (86 +/- 4 mg/dL in Sham rats). The in vitro blood-perfused juxtamedullary nephron technique was used to study renal arteriolar diameter responses to exogenous AngII or K(+)-induced membrane depolarization. 3. Baseline afferent arteriolar diameter did not differ between kidneys harvested from Sham and STZ rats; however, constrictor responses to AngII were accentuated in kidneys from diabetic rats. During exposure to 10 nmol/L AngII, afferent diameter decreased by 37 +/- 5 and 18 +/- 4% in STZ and Sham kidneys, respectively. Efferent arterioles from Sham and STZ rats did not differ with regard to either baseline diameter or AngII responsiveness. 4. In experiments assessing afferent arteriolar responsiveness to membrane depolarization, 40 mmol/L K+ decreased lumen diameter by 73 +/- 11% in kidneys from Sham rats; however, the same depolarizing stimulus only reduced afferent diameter by 28 +/- 7% in STZ kidneys. 5. We conclude that afferent (but not efferent) arteriolar AngII responsiveness is increased during the early stages of poorly controlled diabetes mellitus in the rat. The exaggerated afferent arteriolar responsiveness to AngII occurs despite reduced sensitivity to membrane depolarization, suggesting that the emergence of alternative signalling processes or alterations in vasoactive modulator influences may underlie this phenomenon.     

Renal functional responses to centrally administered ouabain in anesthetized rabbits

The effects of intracerebroventricularly administered ouabain on renal function were studied in rabbits. Ouabain, when given intracerebroventricularly in doses ranging from 0.1 to 10 micrograms/kg, dose-dependently produced antidiuretic, antinatriuretic and antikaliuretic effects, along with decreases in renal perfusion and glomerular filtration rate. Systemic blood pressure also increased significantly in a dose-related fashion. No increase in free water reabsorption was noted. Intravenously administered ouabain (10 micrograms/kg) caused less pronounced antidiuresis and antinatriuresis, with the renal hemodynamics tending slightly to decrease. No significant increment of systemic blood pressure with intravenous ouabain was observed. In rabbits with one kidney denervated and the contralateral left intact, ouabain 10 micrograms/kg i.c.v. produced the typical renal effects on the intact kidney, while the denervated kidney responded with prominent natriuresis and diuresis, showing the maximal response in the second 10-min period after administration. Renal nerve activity increased significantly upon administration of ouabain 10 micrograms/kg i.c.v. and reached a peak at around 10 to 20 min after drug administration, a period in which the most remarkable antidiuresis and antinatriuresis is produced by i.c.v. ouabain. These observations suggest that the antidiuresis and antinatriuresis elicited by centrally administered ouabain results mainly from the decrease of renal hemodynamics, which is caused by the increased renal nerve activity.     

Renal,cardiac, and systemic hemodynamic effects of the dopamine receptor agonist SK&F 85174 in anesthetized dogs

SK&F 85174 is a mixed DA-1/DA-2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital-anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA-1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S-sulpiride (DA-2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA-1 receptors, and (c) whereas DA-1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA-2 receptors also contributes to the hypotension.     

Ethanol alters hemodynamic responses to cocaine in rats

Cocaine is often used while consuming ethanol despite evidence that this combination may enhance the toxicity of cocaine. In the present study, we examined the cardiovascular effects of ethanol (475 or 950 mg/kg, i.v.) alone and in combination with cocaine (5 mg/kg, i.v.) in conscious rats. Ethanol or cocaine administration produced a consistent pressor response but highly variable cardiac output and systemic vascular resistance responses. The hemodynamic response patterns in individual rats to either drug were similar and related within rats. After ethanol pretreatment, cocaine produced greater decreases in cardiac output. We have proposed that this pattern of responses may reflect a predisposition in individual rats to cocaine-induced cardiomyopathies and hypertension. Furthermore, these data suggest that ethanol administration elicits a similar pattern of hemodynamic responses as previously reported for cocaine or amphetamine administration or acute behavioral stress.     

Renal effects of prolonged intrarenal infusions of angiotensin II and atrial natriuretic peptide in sheep.

Angiotensin II (AngII) and atrial natriuretic peptide (ANP) are two hormones that have antagonistic effects on volume and pressure regulation. Plasma levels of both hormones are elevated in sheep pregnancy. However, during pregnancy, volume expansion occurs despite elevated plasma ANP, implying an overriding role of AngII. In addition to counteracting the effects of ANP on the physiological level, AngII also may act on the receptor level. Therefore this study was designed to investigate the hemodynamic and renal effects of ANP and AngII separately and to define their selective effects on the renal natriuretic peptide receptor types in the various segments of the nephron. Eight unilaterally nephrectomized nonpregnant sheep received separately for 10 days, low doses of AngII (1 ng/kg/min) and ANP (0.5 ng/kg/min) directly infused into the renal arteries to avoid systemic effects. Intrarenal AngII infusion decreased sodium excretion (UNaV) from 111+/-11 to 36 +/-8 and 45+/-6 mmol/day (p<0.05) on days 3 and 8-10, respectively. Mean arterial pressure (MAP) increased from 94 +/-6 mm Hg to a maximum of 107+/-8 mm Hg on day 5 of infusion and stabilized at 101+/-7 mm Hg on days 8-10 (p<0.05). Intrarenal ANP infusion significantly increased UNaV on day 1 from 93+/-9 to 188+/-20 mmol/day (p<0.05), followed by sodium retention on days 4-6 (average, 60+/-13 mmol/day; p<0.05). UNaV again increased above control levels on days 8-10 to an average level of 111+/-15 mmol/day. MAP decreased from 99+/-4 to 90+/-5 mm Hg (p<0.05) on days 1-3, and remained lower than control throughout the infusion period. The kidneys were collected at control nephrectomy and at the end of infusion. The natriuretic peptide receptors were characterized by competitive-binding radioreceptor assays on glomerular, outer medullary, and inner medullary membranes. AngII infusion increased the dissociation constant (Kd) of inner medullary natriuretic peptide receptors from 186 +/-11 to 267+/-22 pM (p<0.05), and ANP infusion decreased maximal binding capacity (Bmax) of inner medullary receptors from 134+/-10 to 89+/-15 fmol/mg protein (p<0.05). Glomerular and outer medullary natriuretic peptide receptors were not affected by either AngII or ANP infusion. In conclusion, AngII stimulates antinatriuresis and counteracts the hemodynamic and renal effects of ANP in part by downregulating the renal inner medullary natriuretic peptide receptors.     

Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists.

The vasomotor responses of individual cerebral pial arterioles on the convexity of the cerebral cortex to subarachnoid perivascular micro-injections of dopamine and the putative dopamine receptor agonists, apomorphine, SKF 38393 and LY 141865, have been examined in 38 anaesthetized cats. The perivascular microapplication of dopamine (10(-9)-10(-3)M) effected dose-dependent reductions in pial arteriolar calibre, with the maximum reductions in calibre (22 +/- 2% from preinjection levels: mean +/- s.e.) being observed at 10(-3)M. The cerebrovascular constriction produced by dopamine (10(-5)M) could be significantly attenuated by the concomitant perivascular administration of phentolamine (10(-6)M) or methysergide (10(-6)M). The perivascular microapplication of apomorphine (10(-8)-10(-4)M) effected dose-dependent increases in arteriolar calibre, with the maximum increase (31 +/- 6%) being observed with apomorphine (10(-5)M). The perivascular administration of the putative dopamine D1-receptor agonist, SKF 38393 (10(-9)-10(-4)M) increased arteriolar calibre, with the maximum response (24 +/- 3%) being observed with injection of 10(-7)M. The putative dopamine D2-receptor agonist, LY 141865, also increased cerebral arteriolar calibre, but only at high concentrations (maximum calibre increase 25 +/- 6.1 with 10(-4)M). The cerebrovascular dilatations elicited by apomorphine and by SKF 38393 were markedly attenuated by the concomitant perivascular microapplication of the putative dopamine D1-receptor antagonist, SCH 23390 (10(-8)M). The perivascular administration of SCH 23390 (10(-9)-10(-5)M) per se did not alter arteriolar calibre nor the arteriolar dilatation provoked by microinjections of acidic cerebrospinal fluid. These results point to the presence on cat cerebral arterioles of dopamine receptors (probably of D1 subtype) mediating dilation.     

Renal response to amino acid infusion in rats: effect of dopamine receptor antagonists and benserazide

Previously, we have found that feeding is a dominant factor controlling urinary dopamine excretion (U_DA) in conscious rats (Mühlbauer and Osswald 1992). Since the renal response to feeding is also characterized by an increase in glomerular filtration rate (GFR), we wanted to investigate in a first step whether the feeding-induced elevations of GFR and U_DA could be causally related phenomena. Therefore, we studied the influence of dopamine synthesis and dopamine receptor blockade on the renal response to amino acid infusion (AA) in thiopental anesthetized rats. AA infusion (n = 7) increased GFR by 33±7% (P<0.001) and U_DA by 87±19% (P<0.001). In the presence of benserazide (BZD, n = 5), an inhibitor of dopamine synthesis, infused i.v. at a dose of 30 g/min/kg, U_DA was suppressed to values below detection limit and the AA-induced GFR increase was abolished. Continuous intravenous infusion of the DA₁ receptor antagonist SCH 23390 (SCH, n = 7) in a dose of 4.0 g/kg/min did not prevent the AA-induced increase in GFR (33±3%, P<0.001) and U_DA (97±12%, P< 0.001). In contrast, S-sulpiride (SUL), a specific DA₂ receptor antagonist, infused continuously i.v. in a dose of 5 g/kg/min, completely abolished the AA-induced GFR increase, while U_DA was increased 1.6-fold (P<0.01). Like BZD, both dopamine receptor antagonists did not affect renal sodium excretion substantially.Our results suggest, that endogenous dopamine could act as a mediator in the renal response to amino acid infusion in the rat, most likely by activation of DA₂ receptors. Correspondence to:B. Mühlbauer at the above address     

Centrally mediated cardiovascular responses to intracisternal injections of sympathomimetic amines in anesthetized rats.

The cardiovascular effects resulting from intracisternal (i.c.) injections of sympathomimetic amines were studied in alpha-chloralose-urethanized rats. Norepinephrine (0.5-5 mug i.c.) caused a typical rise in blood pressure with no significant change in heart rate and a fall in blood pressure with a bradycardia, which were completely blocked after treatment with phentolamine (10-50 mug i.c.) L-isoproterenol (0.05-0.5 mug i.c.) and trimetoquinol (0.5-3 mug i.c.), a beta-sympathomimetic agent, usually caused a fall in blood pressure with a tachycardia, which was reduced after treatment with propranolol (10-50 mug i.c.), but trimetoquinol was inclined to cause a rise in blood pressure with a tachycardia. Epinephrine (5 mug i.c.) showed both centrally mediated alpha- and beta-sympathomimetic effects. Tyramine (0.5-1 mg i.c.) caused mixed blood pressure responses presumably due to a release of norepinephrine and epinephrine, and these responses were partially blocked after treatment with phentolamine (100 mug i.c.) or propranolol (50 mug i.c.). These observations suggest that both alpha- and beta-sensitive adrenergic zones may exist on the vasomotor center of the pons and medulla in rats, and both norepinephrine and epinephrine might centrally play a physiological role as the neurotransmitters controlling blood pressure in rats.     

Renal response to infusion of dopamine precursors in anaesthetized rats

In the present study the renal response to intravenous infusion of the catecholamine precursors l-dihydroxyphenylalanine (l-DOPA) or l-tyrosine was investigated in thiopentone sodium-anaesthetized Sprague-Dawley rats. Glomerular filtration rate (GFR) was assessed by renal clearance of inulin, urinary concentration of dopamine (U_DAV) by HPLC and sodium excretion (U_NaV) by flame photometry. We found that basal U_DAV was 6.5 ± 0.5 pmol/min per 100 g body weight (mean ± SEM). Intravenous infusion of l-tyrosine at 0.1–3.0 μmol/min dose dependently enhanced U_DAV (17 ± 3 to 144 ± 14 pmol/ min respectively) with higher doses of l-tyrosine resulting in no further increase in U_DAV. Compared with l-tyrosine administration significantly lower doses of l-DOPA (0.07 to 35 nmol/min) caused increases in U_DAV which were orders of magnitude higher (18 ± 1 to 7800 ± 470 pmol/min, respectively) and did not show saturation characteristics. GFR did not change in response to l-tyrosine or l-DOPA infusion. No variations in urinary flow rate or in U_NaV could be observed which were significantly correlated to changes in U_DAV. In contrast, intravenous infusion of dopamine at a dose of 6 nmol/min significantly increased GFR by 35 ± 6.2% and urinary flow rate by over 2-fold. Immunohistochemistry with light microscopy revealed no tyrosine hydroxylase in the kidney. Therefore, dopamine synthesis in the tubular cells mainly depends on the renal supply of l-DOPA. The unchanged GFR and U_NaV in spite of large variations of U_DAV argue against the hypothesis that intratubular dopamine plays a functional role in the regulation of hemodynamics or sodium transport in the kidney. Renal dopamine excretion may rather represent an effective pathway for the elimination of catecholamine precursors from the plasma. Received: 5 February 1997 / Accepted: 24 July 1997     

Systemic and regional hemodynamic effects of atriopeptin II in anesthetized rats

The hemodynamic and renal effects of atriopeptin II were investigated in rats, using electromagnetic flowmeters and thermodilution and clearance techniques, and its direct cardiac effects were studied in isolated rat atria and ventricular muscle strips. Atriopeptin II had no effect on the rate or force of contraction of rat cardiac tissue in vitro. In anesthetized rats, i.v. injections of 1, 3, 5, and 7 micrograms/kg induced only transient hemodynamic effects: blood pressure (BP) was briefly reduced, and renal blood flow (RBF) but not mesenteric blood flow (MBF) increased. Infusions over 30 min at rates of 0.3, 1, 3, and 10 micrograms/kg/min caused a fall in BP, mediated by a reduction of cardiac output (CO); RBF and MBF were decreased in a dose-related manner, and systemic and regional vascular resistances rose. A reduction of RBF was also observed in clearance experiments, but glomerular filtration rate remained unchanged and the filtration fraction increased significantly. Natriuresis occurred at all rates of atriopeptin tested (0.3, 1, and 3 micrograms/kg/min i.v.) These results suggest that i.v. injection of atriopeptin II induces transient hypotensive and regional vasodilatory effects. Upon i.v. infusion, BP is lowered by way of a reduction in CO, which is accompanied by systemic and regional vasoconstriction. The decrease in CO cannot be ascribed to a direct cardiodepressant action, and the effects on regional blood flows are probably due to reflex activation. The natriuretic effects of atriopeptin II are independent of renal vasodilatation and may be attributable to changes in intrarenal hemodynamics or to direct tubular effects.     

Difference in pressor responses to NG-monomethyl-L-arginine between conscious and anesthetized rats

NG-Monomethyl-L-arginine (L-NMMA; 0.1-10 mg/kg, i.v.), a selective inhibitor of nitric oxide (NO) synthesis derived from L-arginine, elicited a greater increase in blood pressure in urethane/alpha-chloralose- and pentobarbital-anesthetized rats than in conscious Wistar rats. The pressor response to phenylephrine was almost equivalent in both conscious and anesthetized rats. These findings suggest that the experimental conditions (anesthetized or conscious) modify the spontaneously released NO's contribution to blood pressure regulation in vivo.     

Renal hemodynamic responses to 5-hydroxytryptamine (5-HT): involvement of the 5-HT receptor subtypes in the canine kidney

The study was designed to define the serotonin (5-HT) receptor subtypes in the canine kidney. An intrarenal infusion of 5-HT at a dose of 5 micrograms/min in anesthetized dogs resulted in a biphasic response of renal blood flow which decreased transiently then increased above the control level during prolonged infusion. The decrease of renal blood flow was abolished by infusion of methysergide but not by ketanserin, and the subsequent increase was abolished by infusion of either ketanserin or methysergide. Terazosin, an alpha1-adrenoceptor antagonist, did not modify the renal action of 5-HT. These findings suggest that the renal blood flow response induced by 5-HT did not depend on an indirect effect via the sympathetic nervous system, the initial vasoconstriction was mediated via a 5-HT1-like receptor, and that the latter vasodilatation was mediated via a 5-HT2 receptor. The infusion of 5-HT also increased urine flow and urinary excretion of sodium. These increases were reversed by pretreatment with ketanserin and abolished by methysergide. We propose that 5-HT may exert its antidiuretic action via a 5-HT1-like receptor in the tubules but that the renal hemodynamic changes induced by 5-HT may overcome its antidiuretic action. The present results suggest the existence of a 5-HT1-like and 5-HT2 receptor in the renal vasculature and a 5-HT1-like receptor in the renal tubules.     

Differential hemodynamic responses to selective inhibitors of cyclic nucleotide phosphodiesterases in conscious rats.

Selective inhibition of either the low Km cyclic AMP (cAMP) or low Km cyclic GMP (cGMP) phosphodiesterase (PDE) promotes vasorelaxation and, consequently, produces depressor effects. To evaluate the systemic and regional hemodynamic effects of selective inhibitors of these PDE isozymes, CI-930 (0.1-10 mg/kg), an inhibitor of low Km cAMP PDE, or zaprinast (3-30 mg/kg), an inhibitor of low Km cGMP PDE, was given i.v. to conscious, normotensive rats. The rats were chronically instrumented with vascular catheters and either an ultrasonic transit-time flow probe around the ascending aorta or miniaturized pulsed Doppler flow probes around the superior mesenteric and left renal arteries and the abdominal aorta. CI-930 and zaprinast, at cumulative doses of 3 and 30 mg/kg, respectively, produced comparable reductions in mean arterial pressure (-22 +/- 3 and -19 +/- 4 mm Hg, respectively) and total peripheral resistance (-0.41 +/- 0.07 and -0.42 +/- 0.06 mm Hg/ml/min, respectively) but affected other hemodynamic variables differently. CI-930 at 3 mg/kg increased the heart rate (HR), maximal aortic flow acceleration (dF/dt), and peak aortic flow and decreased the stroke volume (SV). Cardiac output (CO) was not affected by CI-930. Zaprinast at 30 mg/kg increased the CO, dF/dt, and peak aortic blood flow. The HR and SV were unaffected by zaprinast. Although both CI-930 and zaprinast increased the dF/dt and peak aortic flow, these parameters were affected more by CI-930 than by zaprinast. CI-930 decreased hindquarter, mesenteric, and renal vascular resistances in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Method for comparison of the hemodynamic effects of equi-antinociceptive oral doses of drugs in anesthetized rats

In a typical flowchart for discovery of novel analgesic (or other) agents, a critical path often involves maximization of the separation of the therapeutic endpoint from known adverse-effect (AE) endpoint(s). Although strategies can easily be designed for in vitro paradigms such as high-throughput screening, extension to in vivo testing can represent a major obstacle to the rapid progression to the next step in development. The problem can be particularly acute when the assessment is required for oral dosing, and when it is not known if the therapeutic and AE mechanism(s) of action are the same. As a case in point, alpha(2)-adrenoceptor (alpha(2)-AR) agonists have potential therapeutic use as analgesics, but they also produce cardiovascular (CV) effects. However, whether the two effects are inexorably linked has not been resolved, particularly for oral administration. The present study used a novel method for comparing the CV effects produced by alpha(2)-AR agonists given by intraduodenal administration to anesthetized rats at fixed ratios of the oral antinociceptive ED(50) dose of each agonist. The technique provided a useful screen of compounds. In addition,there was no correlation between CV endpoints and alpha(2A)-AR affinity, suggesting that oral alpha(2)-AR-mediated analgesia and CV effects might be separable or that other mechanisms might be involved.     

Renal medullary interstitial infusion is a flawed technique for examining vasodilator mechanisms in anesthetized rabbits

INTRODUCTION: In rats, medullary interstitial (IMI) infusion is a useful technique for selective delivery of pharmacological agents to the renal medulla, in both acute and chronic experimental settings. We examined the feasibility of using this technique for delivery of vasodilators in rabbits, since this larger species would provide a number of advantages, particularly in long-term studies of circulatory control. METHODS: Rabbits were anesthetized with pentobarbitone and artificially ventilated. Catheters were placed in a side branch of the renal artery and/or the renal medullary interstitium. Renal blood flow (RBF) was determined by transit-time ultrasound flowmetry, and blood flow in the cortex and medulla was estimated by laser Doppler flowmetry. RESULTS: Pilot studies showed that renal arterial (IRA) infusions of bradykinin (10-300 ng/kg/min) and adenosine (1-10 ng/kg/min) produced only transient renal vasodilatation. IRA infusions of methylamine hexamethylene methylamine (MAHMA) NONOate (100-1000 ng/kg/min) and acetylcholine (10-250 ng/kg/min) produced dose-dependent and sustained increases in RBF and reductions in arterial pressure at the highest doses. However, IMI infusion of the same doses did not consistently increase medullary laser Doppler flux (MLDF). After IRA MAHMA NONOate and IMI acetylcholine, RBF fell to below its resting level. IRA boluses of acetylcholine (10-1250 ng/kg), bradykinin (2-250 ng/kg), and MAHMA NONOate (100-3000 ng/kg) dose-dependently increased RBF and CLDF and MLDF. DISCUSSION: We had previously validated the IMI infusion technique for intramedullary delivery of vasoconstrictors in rabbits. Our present results indicate that this technique has limited application for delivery of vasodilator agents, in part because counterregulatory vasoconstrictor mechanisms are activated.     

Effect of salt loading on aldosterone response to long-term infusion of angiotensin II in rats.

We examined changes in plasma aldosterone level and blood pressure (BP) after long-term (12 days) intravenous infusion of angiotensin II (Ang II; 15 and 60 ng/min) with two different sodium intakes (0.66% and 8% salt-containing diet) in Wistar rats. Without salt loading, 15 ng/min of Ang II did not increase mean BP (112 +/- 1 vs. 112 +/- 2 mm Hg), but 60 ng/min of Ang II increased mean BP (144 +/- 3 mm Hg, p less than 0.01). However, the 8% salt diet not only enhanced the pressor effect of 60 ng/min Ang II (168 +/- 9 mm Hg, p less than 0.05), but also elevated mean BP with 15 ng/min of Ang II (159 +/- 3 mm Hg, p less than 0.01). On a normal-salt diet (0.66%), plasma aldosterone was increased by Ang II infusion from 11.3 +/- 0.3 ng/dl to 12.7 +/- 0.5 ng/dl (NS) at a rate of 15 ng/min Ang II, and to 15.7 +/- 0.4 ng/dl (p less than 0.01) at 60 ng/min Ang II. However, salt loading reduced Ang II-induced elevation of aldosterone: 11.3 +/- 0.5 ng/dl (less than 0.01) at a rate of 60 ng/min Ang II. Thus, salt loading diminished aldosterone response to Ang II, which might compensate salt-induced enhancement of the pressor effect of Ang II.     

Participation of angiotensin receptors in acute hypoxia in mice. I. Effects of angiotensin peptide receptor ligands saralasin and sarmesin.

The effects of angiotensin II (Ang II) and angiotensin receptor ligands sarmesin ([Sar1, Tyr(Me)4] Ang II) and saralasin ([Sar1, Ala8] Ang II) administered intracerebroventricularly (i.c.v.) on acute anoxic hypoxia were studied in mice. The interactions of these ligands and of amastatin (an aminopeptidase A inhibitor) after pretreatment with Ang II and sarmesin, respectively, were also studied. Ang II decreased the latency to hypoxia-induced convulsive seizures and altered survival time (increase or decrease depending on the dose). Sarmesin and saralasin significantly increased the latency to seizures as well as survival time. Pretreatment with saralasin and sarmesin antagonized the Ang II effect on the latency to seizures. Both drugs increased the Ang II effect on the survival time. Amastatin tended to increase the effect of sarmesin on the survival time. Taken together, the results suggest that the antihypoxic effect of sarmesin and saralasin is most likely due to an action on Ang II receptors, with the agents behaving as partial agonists.     

Vasopressor and heart rate responses to systemic administration of bombesin in anesthetized rats

The aim of the present study was to investigate the effects of aortic depressor nerve (ADN) transection, supranodosal vagi denervation (NG vagi cut) and adrenergic receptor blocker treatment on the cardiovascular responses evoked by systemic injection of bombesin. The cardiovascular effects were studied in spontaneously breathing rats that were (i) bilaterally, midcervically vagotomized (MC vagi cut) and subjected to section of the aortic depressor nerves, (ii) midcervically vagotomized and subsequently vagotomized at the supranodosal level or (iii) midcervically vagotomized before and after pharmacological blockade of α- or β-adrenergic receptors with phentolamine and propranolol, respectively. An intravenous bolus of bombesin (10 μg/kg) in midcervically vagotomized and ADN denervated animals increased mean arterial blood pressure (MAP) and heart rate (HR). An approximate 20% increase in blood pressure occurred immediately following bombesin injection and lasted for 2-3 min. Augmentation of the heart rate occurred 30-60 s after the bombesin challenge and persisted for more than 10 min. After section of the supranodosal vagi, bombesin failed to induce an increase in heart rate. Blockade of α-adrenergic receptors with an intravenous dose of phentolamine significantly reduced post-bombesin hypertension. These results indicate that bombesin-evoked increases in blood pressure do not require aortic depressor nerves and supranodosal vagi and are presumably mediated by the activation of peripheral α-adrenergic receptors. Bombesin-induced tachycardia was dependent on an intact supranodose pathway and was amplified by activation of β-adrenoceptors.