Characterization of the biphasic blood pressure response to alpha-methyl-5-hydroxytryptamine in anaesthetized rats.

The aim of the present study was to investigate the mechanism of the biphasic blood pressure response to the 5-hydroxytryptamine2 (5-HT2) receptor agonist, alpha-methyl-5-HT (alpha-Me-5-HT) in anaesthetized rats. In conscious rats, 5-HT (2.5-15 micrograms/kg, i.v.) produced typical triphasic blood pressure responses at the higher doses. In anaesthetized rats, 5-HT produced only hypotensive responses at all doses. In conscious rats, i.v. injections of alpha-Me-5-HT (5-125 micrograms/kg) produced dose-dependent increases in mean arterial pressure with concomitant bradycardia. However, in inactin-anaesthetized rats, alpha-Me-5-HT produced biphasic blood pressure responses consisting of an initial pressor response followed by a longer lasting depressor phase. In anaesthetized rats, the 5-HT1A antagonist, spiroxatrine (1 mg/kg), and the 5-HT3 receptor antagonist, MDL72222 (0.3 mg/kg), selectively diminished the hypotensive phase without affecting the pressor phase. The 5-HT1/5-HT2 antagonist, methysergide (0.5 mg/kg), and the selective 5-HT2 antagonist, ketanserin (50 micrograms/kg), completely abolished all responses to alpha-Me-5-HT. Pretreatment with the 5-HT-selective uptake inhibitor, fluoxetine (1 mg/kg), produced a significant attenuation of the hypotensive response whilst enhancing the pressor response. Pretreatment with the 5-HT depletor, p-chlorophenylalanine (3 x 100 mg/kg/day), produced an attenuation of the hypotensive phase while the pressor response was augmented. The selective 5-HT2/5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2- amino-propane (5-200 micrograms/kg, i.v.), produced dose-dependent pressor responses in anaesthetized rats but no hypotensive responses were observed. The results show that the 5-HT2 agonist, alpha-Me-5-HT, produces a biphasic blood pressure response in anaesthetized rats which is not seen in conscious rats. The hypotensive response is due to a nonselective activation of 5-HT1 and 5-HT3 receptors through release of 5-HT.

5-Carboxamidotryptamine attenuates the development of deoxycorticosterone acetate-salt hypertension in rats.

The effect of chronic i.v. infusion of the 5-HT1 receptor agonist, 5-carboxamidotryptamine (5-CT), was evaluated during the development of deoxycorticosterone acetate-salt (DOCA-salt) hypertension in rats over 4 weeks. Vehicle-treated (n = 10) Sprague-Dawley rats given DOCA (100 mg/kg, s.c.) and 1% saline as drinking fluid developed hypertension with systolic blood pressure reaching 194.6 +/- 8.99 mm Hg at 27 days. In DOCA-salt rats treated with 5-CT infusions (15.0 micrograms/kg per day, n = 10) for 4 weeks via osmotic minimpumps, systolic blood pressure was significantly lower by 41.7 mm Hg at day 27 when compared to vehicle-treated DOCA-salt rats. Systolic blood pressure values on day 27 in 5-CT-treated DOCA-salt rats were however greater than those in vehicle-treated control rats which were not given DOCA. Systolic blood pressure in 5-CT-treated DOCA-salt rats was significantly lower by day 7 compared to vehicle-treated DOCA-salt rats and remained lowered for the rest of the observation period. Heart rate was significantly greater in 5-CT-treated DOCA-salt rats on day 7 when compared to vehicle-treated DOCA-salt rats. Baroreflex sensitivity on day 28 was significantly greater in 5-CT-treated DOCA-salt rats as compared to vehicle-treated DOCA-salt rats. On day 28, hypotensive responses to hexamethonium (20 mg/kg) in 5-CT-treated DOCA-salt rats were markedly reduced compared to those in vehicle-treated DOCA-salt rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in the chronic hypotensive mechanism of action of ketanserin in spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: To investigate the hypotensive effect and mechanism of action of chronic administration of ketanserin in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. METHODS AND RESULTS: SHR and WKY rats were given chronic ketanserin infusions via osmotic minipumps to minimize fluctuations in drug concentrations and receptor responsiveness. In SHR treated with intravenous infusions of 3.0 (n = 9) or 6.0 mg/kg per day (n = 8) ketanserin for 7 days, significant dose-dependent falls in systolic blood pressure (SBP) were observed during the infusion period. Heart rate did not change in either the vehicle- or the ketanserin-treated groups of SHR. In WKY rats intravenously infused with 3.0 (n = 9) or 6.0 mg/kg per day (n = 10) ketanserin, dose-dependent falls in SBP were also observed during the infusion period, with the changes reaching statistical significance at the 6.0 mg/kg per day dose. The changes in heart rate were not different from those in control rats. Pressor responses to the type 2 5-hydroxytryptamine (5HT2)-receptor agonist (+/-)-alpha-methyl-5-hydroxytryptamine (5.0-125.0 micrograms/kg), as assessed on day 7, were reduced dose-dependently in all ketanserin-infused rats. alpha 1-Adrenoceptor responses to 1.0-10.0 micrograms/kg intravenous phenylephrine were attenuated in only the WKY rats infused with 6.0 mg/kg per day ketanserin. In the SHR treated with ketanserin there was no change in the pressor responsiveness to phenylephrine. Baroreflex sensitivity on day 7 was significantly greater in the ketanserin-infused SHR than in their respective controls. Changes in baroreflex sensitivity were not significantly different in WKY rats following ketanserin infusion. CONCLUSIONS: These results show that chronic administration of ketanserin lowers blood pressure in both SHR and WKY rats. In SHR the alpha 1-adrenoceptor-blocking effects of ketanserin are compensated for, and the reduction in blood pressure by day 7 is maintained predominantly by, 5HT2-receptor blockade. In WKY rats ketanserin-induced hypotension is associated with concomitant blockade of 5HT2- and alpha 1-receptors. The present study therefore suggests a differential mechanism of action of ketanserin in hypertensive and normotensive rats during chronic treatment.

Hydroxyl radical footprinting of calicheamicin. Relationship of DNA binding to cleavage.

The binding to DNA by calicheamicin epsilon (CLM epsilon), the rearranged and reduced product of the diynene antitumor antibiotic calicheamicin gamma 1I (CLM gamma 1I), was studied using the method of hydroxyl radical footprinting. The drug binding sites determined in this way were compared to locations of double-stranded DNA cleavage by thiol-activated CLM gamma 1I. The results of these experiments show that CLM epsilon lies in the minor groove in an extended conformation protecting approximately four nucleotides on each strand of DNA. Sites of CLM epsilon binding correlate to sites of CLM gamma 1I cleavage with protection by CLM epsilon occurring mainly to the 3' side of the site of C5' hydrogen abstraction. From these results, it is possible to propose global structures of the drug/DNA complexes such that the oligosaccharide side chain is arrayed to the 3' side of the site of C5' hydrogen abstraction. This conclusion is entirely consistent with the results of recent atom-transfer experiments [Hangeland, J.J., De Voss, J.J., Heath, J.A., Townsend, C.A., Ding, W.-D., Ashcroft, J., & Ellestad, G.A. (1992) J. Am. Chem. Soc. 114, 9200-9202]. Somewhat greater protection on the strand undergoing C5' hydrogen abstraction was observed to the 5' side of the site of attack owing presumably to proximity of the methyl carbamate portion of the drug with DNA. Overall, binding is seen where cleavage is seen in accord with thermodynamics of drug association to DNA being important in determining the sites of cleavage.

Antihypertensive effect of chronic i.v. administration of 5-carboxamidotryptamine in spontaneously hypertensive rats.

The effects of chronic i.v. administration of the serotonin 5-HT1 receptor agonist, 5-carboxamidotryptamine (5-CT), on blood pressure (BP), heart rate (HR) and baroreflex sensitivity were studied in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Acute i.v. injection of increasing doses of 5-CT resulted in a dose-dependent reduction in mean arterial pressure (MAP) in SHR and WKY with concomitant tachycardia. In chronic experiments, 5-CT (15.0 micrograms/kg per day) or vehicle (24.0 microliters/day) was infused i.v. for 7 days, using osmotic minipumps. Systolic blood pressure (SBP) and HR were monitored daily before and during infusions. In SHR (n = 8) and WKY rats (n = 9) receiving 5-CT, a significant reduction in SBP was observed during the infusion period. HR was slightly increased in WKY rats on days 1 and 2. There were no HR changes in the SHR group. The fall in SBP was significantly larger in the SHR than in the WKY rats. Baroreflex sensitivity on day 7 was significantly greater in 5-CT-treated SHR than in control rats. There was no change in baroreflex sensitivity in WKY rats. Administration of a single dose of 5-CT (0.5 microgram/kg i.v.) on day 7 of infusion resulted in attenuated responses in WKY rats while SHR responded as their respective controls. Our data suggest that chronic administration of 5-CT results in a sustained antihypertensive effect. This is associated with an improved BRS in the SHR either as a consequence of a resetting of the baroreflex due to sustained lowering of BP or a direct action of 5-CT on baroreflex sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in the acute and chronic antihypertensive mechanism of action of ketanserin in spontaneously hypertensive rats.

The antihypertensive mode of action of the 5HT2 receptor antagonist, ketanserin (KET), is still a subject of controversy and has been evaluated predominantly in acute studies. Acute i.v. administration of KET (3.0 or 6.0 mg/kg) in spontaneously hypertensive rats resulted in dose-dependent reductions in mean arterial pressure accompanied by concomitant bradycardia. In these studies, the responses to single i.v. doses of the alpha-1 adrenoceptor agonist phenylephrine (10.0 micrograms/kg) and to the 5HT2 receptor agonist alpha-methyl-5-hydroxytryptamine (125.0 micrograms/kg) 30 min after injection of KET were blocked. In spontaneously hypertensive rats treated with KET infusions (3.0 mg/kg/day i.v., n = 9, or 6.0 mg/kg/day i.v., n = 8) for 7 days via osmotic minipumps, significant dose-dependent falls in systolic blood pressure were observed during the period of infusion. Heart rate did not change over the period of observation in both vehicle- and KET-treated groups. On day 7 of infusion, KET dose-dependently reduced responses to the 5HT2 agonist alpha-methyl-5-hydroxytryptamine (5.0-125.0 micrograms/kg i.v.) but did not affect responses to phenylephrine (1.0-10.0 micrograms/kg i.v.). Baroreflex sensitivity on day 7 was significantly greater in KET-infused rats as compared with control rats. These data confirm that the acute antihypertensive effects of KET are due to a combination of alpha-1 and 5HT2 receptor blockade. During chronic administration, however, the alpha-1 blocking effects of KET are compensated for, and the reduction in blood pressure by day 7 of KET chronic administration is maintained predominantly by persistent blockade of 5HT2 receptors.

Evaluation of a potent inhibitor of subprimate and primate renins.

Our attempts to synthesize a potent inhibitor of rat renin have resulted in the discovery of CGP 44 099 A, a potent inhibitor of plasma renin from all subprimate species tested so far [IC50 (in nM): dog, 0.007; rabbit, 0.033; guinea pig, 0.34; mouse, 0.4; cat, 0.57; and rat, 1.3]. This compound is also a potent inhibitor of primate renins [IC50 (in nM): human, 0.3; and marmoset, 1.4]. It is less potent against other aspartic proteinases [IC50 (in nM): porcine pepsin, 26; and bovine cathepsin D, 230). CGP 44 099 A exhibited a competitive mode of inhibition against human renin (Ki, 0.12 nM). During i.v. infusion of CGP 44 099 A in sodium-depleted normotensive rats (0.1 mg/kg/min) blood pressure (BP) was lowered by about 25 mm Hg. Plasma renin activity, angiotensin I and angiotensin II were almost completely suppressed. The converting enzyme inhibitor enalaprilat (1 mg/kg i.v.) also lowered BP by about 25 mm Hg. No further fall in BP occurred when CGP 44 099 A (0.1 mg/kg/min) was infused after pretreatment with enalaprilat (1 mg/kg i.v.) and CGP 44 099 A did not lower BP when infused in bilaterally nephrectomized rats. These results indicate that the hypotensive response induced by CGP 44 099 A in sodium-depleted rats is specifically due to the renin inhibition. Compounds such as CGP 44 099 may therefore be useful for comparing the effects of renin inhibition in different species and for studying the role of renin in various models of cardiovascular disease in nonprimate species.

Comparison of the acute hypotensive effects of renin inhibition, converting enzyme inhibition, and angiotensin II antagonism in rats.

The purpose of this study was to compare the acute hypotensive efficacy of different types of inhibitor of the renin-angiotensin system. A renin inhibitor (RI), CGP 44,099 A, a converting enzyme inhibitor (CEI), enalaprilat, a peptidic angiotensin II (Ang II) antagonist, [Sar1, Ile8]Ang II (P-Ang IIA), and a nonpeptidic Ang II antagonist devoid of agonistic properties, 2-butyl-4-chloro-1- ([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl)-5- (hydroxymethyl)imidazol (NP-Ang IIA), were administered intravenously to sodium-depleted rats (SDRs), renal hypertensive rats (two-kidney, one-clip) (RHRs), and spontaneously hypertensive rats (SHRs). The four compounds were all effective in lowering blood pressure (BP) in SDRs and RHRs. The maximum hypotensive response observed within 30 min of administration was similar for all four compounds (approximately 30 mm Hg in SDRs and 60 mm Hg in RHRs). In SHRs, the P-Ang IIA induced a pressor response whereas the RI, CEI, and NP-Ang IIA lowered BP to a similar extent (approximately 15 mm Hg). Pretreatment with the CEI completely prevented the hypotensive response to RI in SHRs, and vice versa. These observations indicate that the principal mechanism by which converting enzyme inhibitors lower BP after acute administration in these rat models is by inhibition of the formation of Ang II. The pressor response to the P-Ang IIA in SHRs is probably a consequence of its partial agonistic properties. Renin inhibitors and nonpeptidic Ang II antagonists, devoid of agonistic properties, promise to be effective antihypertensive agents similar to the CEIs.

Biologic response to chronic blockade of vasopressin receptors in Sprague-Dawley rats.

The renal tubular arginine vasopressin receptor antagonist, d-(CH2)5-D-Tyr(Et)VAVP, is a potent inhibitor of the vasopressin-induced stimulation of adenylate cyclase in rat renal medullary homogenates in vitro. In acute experiments in vivo, this antagonist increased urine volume and decreased urine osmolality after i.v. or s.c. administration in normally hydrated or dehydrated Sprague-Dawley rats. It did not show any effects in water-loaded rats. The duration of action of the antagonist was between 3 to 4 hr. Chronic i.v. infusion or repeated s.c. injections did not result in a persistent diabetes insipidus. A transient rise in water excretion was followed by a progressive normalization. The marked initial water loss was fully compensated for by an increased water intake so that plasma volume and extracellular fluid volume remained unchanged. After 1 week of treatment with the antagonist, glomerular filtration rate and plasma renin activity were not significantly different from base-line values. Only small functional deficits in renal concentrating capacity became manifest when drinking water was withheld. It is possible that the activation of endogenous compensatory mechanisms restored water balance during chronic arginine vasopressin receptor blockade. An intrinsic agonism of this antagonist, which was not detectable in acute experiments, might have contributed to the normalization of water balance by limiting the maximum anti-antidiuretic effects of renal tubular arginine vasopressin receptor blockade.

Evaluation of the pharmacologic properties of a vasopressin antagonist in Brattleboro rats.

The arginine vasopressin (AVP) analog d-(CH2)5-D-Tyr(Et)VAVP is a potent competitive antagonist of AVP at renal tubular AVP receptors. In Sprague-Dawley rats, this compound induces diuresis after single injections but only a transient diabetes insipidus-like state during continuous infusion. To further evaluate the pharmacologic profile of d-(CH2)5-D-Tyr(Et)VAVP, the present experiments were performed in Brattleboro rats homozygous for hereditary hypothalamic diabetes insipidus. In these rats, acute and chronic administration of the antagonist induced significant antidiuretic effects. These agonistic effects persisted for up to 4 days after single injections and for more than 2 weeks after stopping continuous infusions. The antidiuretic effects of the antagonist during chronic administration were indistinguishable from those of AVP replacement. When the renal tubular AVP receptor antagonist was infused into diabetes insipidus rats that had received AVP for 1 week, it induced a transient rise in water intake. However, the peak values after administration of the antagonist were much lower than after AVP withdrawal. These observations suggest that d-(CH2)5-D-Tyr(Et)VAVP has substantial agonistic properties that are not detectable in Sprague-Dawley rats except for limiting the compound's maximum anti-antidiuretic efficacy. These agonistic effects together with endogenous compensatory mechanisms may allow Sprague-Dawley rats to maintain a normal water balance during the continuous administration of d-(CH2)5-D-Tyr(Et)VAVP.

[3H]AVP binding to rat renal tubular receptors during long-term treatment with an antagonist of arginine vasopressin.

The interaction of an antagonist of arginine vasopressin (AVP), d(CH2)5-D-Tyr(Et)VAVP, with renal tubular V2 receptors were studied in medullary membrane preparations from kidneys of Sprague-Dawley and Brattleboro rats. In both rat strains, V2 receptors had comparable KD and Bmax values for binding of [3H]AVP. In vitro studies revealed that the V2-antagonist was more potent than cold AVP in displacing [3H]AVP. In vivo treatment of Sprague-Dawley rats with the antagonist over one week resulted only in a transient state of diabetes insipidus (DI). No specific [3H]AVP binding was detectable throughout the period of administration. Chronic treatment of Brattleboro rats resulted in a complete normalization of water intake. This agonistic effect was also associated with undetectable [3H]AVP binding. After stopping the infusion of d(CH2)5-D-Tyr(Et)VAVP, Bmax values tended to rise but had still not reached base line values after 6 days. In contrast, the chronic infusion of AVP in Brattleboro rats resulted in a reduction in water intake which was accompanied by a decreased Bmax. [3H]AVP binding remained detectable during the entire treatment period. Thereafter Bmax was restored to base line values within 2 days of stopping the infusion. These results suggest that d(CH2)5-D-Tyr(Et)VAVP has a high affinity for V2 receptors in both Sprague-Dawley and Brattleboro rats. Its rate of dissociation from the receptor appears to be much slower than that of AVP. In Brattleboro rats, the binding of d(CH2)5-D-Tyr(Et)VAVP leads to an antidiuretic response. In Sprague-Dawley rats, a transient diuretic response is followed by a progressive normalization in water intake. This occurs despite persistent and complete blockade of renal medullary V2 receptors.

Alterations in responsiveness of noradrenergic neurons of the locus coeruleus in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

Locus coeruleus may have a function in central blood pressure regulation and possibly in the pathogenesis of hypertension. In keeping with this notion, we have recently shown that deoxycorticosterone acetate (DOCA)-salt hypertensive rats demonstrate a greater increase in blood pressure induced by locus coeruleus stimulation than control animals. In an attempt to elucidate the underlying mechanisms leading to this alteration in responsiveness of the locus coeruleus, the sensitivity of noradrenergic neurons of the locus coeruleus to the transmitter candidates, epinephrine and glutamate, was investigated in DOCA-prehypertensive (3 days post-DOCA), DOCA chronic hypertensive (6-8 weeks post-DOCA) and control rats using conventional microiontophoretic and single cell recording techniques. Iontophoretically applied epinephrine produced a current-dependent decrease in spontaneous firing rate of all noradrenergic neurons in both DOCA-treated and control rats. Locus coeruleus neurons of DOCA-treated rats at 3 days and 6-8 weeks were less sensitive to epinephrine than those of control rats and the magnitude of the depression in spontaneous firing rate was less. By contrast, iontophoretic applications of glutamate produced an increase in activity of all noradrenergic locus coeruleus neurons. However, there was minimal difference in glutamate sensitivity between neurons of DOCA and control rats. Since the changes in epinephrine sensitivity are apparent not only in the chronic stage but also in the prehypertensive stage, our findings suggest a potential role of the adrenergic input to the locus coeruleus in the pathogenesis of DOCA-hypertension.

Acute and chronic haemodynamic and natriuretic effects of atriopeptin II in conscious rats.

The haemodynamic and natriuretic effects of an atrial natriuretic peptide were studied in conscious rats during acute and chronic administration of the peptide. Infusion of atriopeptin II (0.3 microgram/kg per min intravenously) for 60 min produced a fall in blood pressure and a rise in heart rate, accompanied by a significant decrease in renal and mesenteric blood flow. Despite the renal vasoconstriction, urinary sodium excretion increased markedly. These findings suggest that the hypotensive effect of atriopeptin II in conscious rats is not mediated by systemic vasodilatation, and that renal vasodilatation is not a prerequisite for the natriuretic action of this peptide. During infusion of atriopeptin II (24 micrograms/day) for 2 days, a small but persistent hypotensive effect was observed, which was accompanied by transient tachycardia. However, infusion of the same, or a higher (120 micrograms/day), dose of atriopeptin II for 4 days failed to produce any natriuretic effects. These results suggest that atrial natriuretic peptides are more important in acute than in chronic regulation of sodium excretion.

Chronic blockade of vasopressin receptors in rats.

Chronic i.v. administration of a competitive antagonist of arginine-vasopressin (AVP), d(CH2)5-D-Tyr(Et)-VAVP, in Sprague-Dawley rats induced only a transient diabetes insipidus (DI)-like state. Water excretion and intake were markedly increased on the first day of administration but subsequently reverted to normal. A similar response to the antagonist was observed upon continuous i.v. infusion in Brattleboro rats, homozygous for hereditary hypothalamic DI, which had been substituted with exogenous AVP. This excludes the possibility that increased secretion of endogenous AVP had overcome the blocking effect of the competitive antagonist in Sprague-Dawley rats. However, when AVP was withdrawn from chronically AVP-treated DI rats, water intake increased to values higher than those observed after the antagonist. Subsequently, water intake also decreased but remained elevated compared to that of AVP-substituted rats receiving the antagonist. This suggests that the antagonist might have AVP-like agonistic properties that limit its efficacy and allow compensatory mechanisms to restore normal water balance despite continuous blockade of AVP receptors. The agonistic properties of d(CH2)5-D-Tyr(Et)VAVP were verified upon chronic i.v. administration in nonpretreated DI rats. Thus, the normalization of water balance in Sprague-Dawley rats chronically receiving d(CH2)5-D-Tyr(Et)VAVP is probably due to the activation of compensatory mechanisms and to the agonistic effects of d(CH2)5-D-Tyr(Et)VAVP.

Cardiovascular effects of intracerebroventricular injection of vasopressin in unanaesthetized normotensive and DOCA-salt hypertensive rats.

The mean arterial pressure (MAP) and heart rate (HR) responses to intracerebroventricular (i.c.v.) administration of arginine vasopressin (AVP) in unanaesthetized normotensive control and DOCA-salt hypertensive rats were studied. Intracerebroventricular administration of AVP (0.25-1000 ng) to control rats produced dose-dependent long-lasting increases in MAP (5-45 mmHg) and HR (35-110 beats/min). Peripheral treatment of rats with an antipressor AVP antagonist had no effect on i.c.v. AVP-induced increases in MAP and HR, whereas the responses were blocked by i.c.v. administration of the antagonist. Peripheral administration of phentolamine and propranolol also completely blocked the changes in MAP and HR. DOCA-salt hypertensive rats showed significantly greater increases in MAP and HR in response to i.c.v. AVP and a tenfold lower threshold for stimulation. The results demonstrate that AVP acting on central neural structures can produce increases in MAP and HR by stimulating sympathetic outflow. Increased sensitivity and responsiveness to i.c.v. AVP in hypertensive rats suggest a potential mechanism of action of AVP in hypertension.

Contribution of vascular and tubular effects of arginine-vasopressin to the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats.

The role of arginine-vasopressin (AVP) in the pathogenesis of deoxycorticosterone acetate (DOCA) salt hypertension in rats was studied with AVP receptor antagonists for its tubular (V2) and/or vascular (V1) actions. When chronic (six weeks) infusion of the antagonists was started concomitantly with DOCA-salt treatment the development of hypertension was attenuated by the V1-antagonist and prevented by the V1V2-antagonist. However, the V1V2-antagonist induced severe and persistent hypernatraemia in all rats. When chronic (two weeks) infusion of the antagonists was started in rats with established hypertension after five weeks of DOCA-salt treatment blood pressure was not influenced by the V1-antagonist. The rats which received the V1V2-antagonist died from hypernatraemia within four days. These results suggest that in DOCA-salt treated rats AVP is essential for the prevention of severe and life-threatening hypernatraemia. AVP appears to contribute significantly to the development of this form of hypertension through both its vascular and tubular effects.

Endocrine control of salt and water excretion: the role of vasopressin in DOCA-salt hypertension.

Arginine-vasopressin (AVP), the antidiuretic hormone, not only regulates water balance but may also exert direct and indirect effects on blood pressure by influencing systemic vascular resistance and body fluid volumes. Recently, specific competitive antagonists of AVP at its vascular and tubular receptors have been described. We used d(CH2)5Tyr(Me) AVP, a vascular (V1) antagonist, and d(CH2)5-D-Tyr(Et) VAVP, a vascular and tubular (V1V2) antagonist, for studies on the role of AVP in deoxycorticosterone acetate (DOCA)-salt hypertension. The antagonists were infused intravenously via osmotic minipumps in unilaterally nephrectomized rats for 6 weeks after the beginning of the DOCA-salt treatment. At the end of the experiment, blood pressure was 15 mm Hg lower in the rats receiving the V1 antagonist than in those in which the vehicle was infused. In the rats receiving the V1V2 antagonist, blood pressure was reduced by 38 mm Hg. However, these rats were in poor general condition and gained no body weight. Their plasma sodium concentration was markedly increased throughout the duration of the experiment. These results suggest that AVP contributes to the development of DOCA-salt hypertension not only through its vascular but also through its renal tubular effects. Thus AVP may act as an impormediator of volume changes associated with alterations in sodium intake or excretion and thereby affect blood pressure.

The significance of vasopressin as a pressor agent.

The antidiuretic hormone, arginine-vasopressin (AVP), may participate in the regulation of blood pressure (BP) through its vasoconstrictor effects. In anesthetized rats, exogenous AVP induced stronger vasoconstriction in the mesenteric than in the renal vascular bed. Conversely, mesenteric but not renal vascular resistance was reduced by a vascular antagonist of AVP, d(CH2)5 VDAVP, in rats with increased endogenous AVP after anesthesia, dehydration, or injection of glycerol. Another vascular AVP-antagonist, d(CH2)5 Tyr (Me) AVP, induced a transient fall in BP in conscious primates (marmosets) after diuretic-induced volume depletion. In conscious rats with established deoxycorticosterone acetate (DOCA)/salt hypertension, d(CH2)5 Tyr (Me) AVP decreased systolic BP after acute administration. After chronic administration of this antagonist during 6 weeks after the beginning of DOCA/salt treatment, the severity of hypertension was reduced. When another, AVP-antagonist, d(CH2)5-D-Tyr (Et) VAVP, which blocks vascular and renal tubular AVP-receptors, was administered chronically, the development of DOCA/salt hypertension was prevented at the expense of severe and persistent hypernatremia. These results demonstrate that under certain conditions the vascular effects of AVP may contribute to the maintenance of BP, AVP appears to participate in the pathogenesis of DOCA/salt hypertension through both its vasoconstrictor and its antidiuretic effects.