saralasin and Hyponatremia

Topics: Angiotensin II; Animals; Blood Pressure; Hypertension, Malignant; Hypertension, Renal; Hyponatremia; Juxtaglomerular Apparatus; Osmolar Concentration; Pepstatins; Plasma Volume; Rats; Renin; Saralasin; Vasopressins; Water-Electrolyte Imbalance

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Hypertension; Hyponatremia; Infusions, Parenteral; Male; Metolazone; Middle Aged; Renin; Saralasin; Sodium; Spironolactone

1. Angiotensin II blockade before and after marked sodium depletion in patients with hypertension [unilateral renovascular (eight), bilateral renovascular (four) and essential (four)] was performed by intravenous administration of the angiotensin II antagonist Sar1-Ala8-angiotensin II (saralasin). 2. On normal sodium intake, saralasin decreased mean blood pressure by 8 mmHg in the unilateral renovascular group, by 6 mmHg in the bilateral renovascular group and increased it by 3 mmHg in the essential hypertensive group. After sodium depletion saralasin decreased mean blood pressure by 33 mmHg, 35 mmHg and 18 mmHg respectively. The saralasin-induced decrease in blood pressure significantly correlated with the log of the initial plasma renin activity. 3. Saralasin infusion decreased effective renal plasma flow (ERPF) in all three hypertension subgroups, both on normal sodium intake and after sodium depletion. Glomerular filtration rate decreased in direct relation to the hypotensive effect of saralasin but ERPF showed this relationship only after sodium depletion. On normal sodium intake saralasin increased filtration fraction by 17%, but decreased it by 7% after sodium depletion. 4. It is concluded that the hypotensive action of saralasin closely correlates with the value of circulating plasma renin activity, apparently independent of the aetiology of the hypertension. The decrease in ERPF during saralasin infusion in the patients on normal sodium intake seems mainly related to the agonistic activity of saralasin, but that after sodium depletion to the hypotensive effect of saralasin.

Topics: Adult; Angiotensin II; Blood Pressure; Female; Hemodynamics; Humans; Hypertension; Hyponatremia; Kidney; Male; Middle Aged; Renin; Saralasin

Previous work had shown that halothane and enflurane at 1 MAC and ketamine, 125 mg/kg, did not increase plasma renin activity (PRA) in the normal sodium-replete rat. To investigate the renin-angiotensin system with increased PRA, 25 rats were fed a low-sodium diet for five to seven days and divided into four groups: awake; halothane, 1.26 vol per cent; enflurane, 1.75 vol per cent; ketamine, 125 mg/kg, intramuscularly. The protocol consisted of a two-hour awake period, then an hour of stable anesthesia, followed by 30 min infusion of saralasin, an angiotensin II competitive inhibitor. An additional 18 rats had PRA measured by radioimmunoassay before and after an hour of stable anesthesia. Stable anesthesia decreased mean arterial pressure from 122 +/- 2 to 69 +/- 4 torr for the halothane group, 70 +/- 3 torr for the enflurane group, and 103 +/- 7 torr for the ketamine group. When saralasin was infused for 30 min, blood pressure decreased to 100 +/- 3 torr for the awake group, 40 +/- 1 torr for the halothane group, 44 +/- 2 torr for the enflurane group, and 73 +/- 3 torr for the ketamine group. PRA increased from 4.3 +/- 0.5 ng/ml/hr for sodium-replete rats to 12.9 +/- 1.7 ng/ml/hr for sodium-depleted rats. After an hour of stable anesthesia, PRA increased in all the anesthetized groups. The authors conclude that the anesthetic agents studied increase renin release in the sodium-depleted rat. The initial renin level may be important in determining whether changes in renin release occur with anesthetic agents.

Topics: Anesthetics; Animals; Blood Pressure; Blood Volume; Diet, Sodium-Restricted; Enflurane; Halothane; Hyponatremia; Ketamine; Male; Rats; Renin; Saralasin

Topics: Aldosterone; Angiotensin II; Animals; Corticosterone; Desoxycorticosterone; Extracellular Space; Hypertension; Hypertension, Renal; Hyponatremia; Rats; Renal Artery Obstruction; Renin; Saralasin; Sodium; Sodium Chloride; Teprotide

The aldosterone and arterial pressure response to long-term infusion of two angiotensin II inhibitory analogues, [Sar1,Ala8]angiotensin II and [Sar1,Ile8]angiotensin II, and the angiotensin I-converting enzyme inhibitor, SQ 20,881, was studied in conscious dogs during sodium deficiency. Plasma aldosterone concentration (PAC), plasma cortisol concentration (PCC), and plasma renin activity (PRA) were determined by radioimmunoassay. In conscious dogs after dietary sodium restriction (5 mEq of Na+/day) for 21 days, PAC averaged 37.5 +/- 8.9 (mean +/- SE) ng/dl, PCC averaged 1.3 +/- 0.5 microng/dl, PRA averaged 3.23 +/- 0.42 ng/ml per hour, and arterial blood pressure (AP) averaged 103 +/- 5 mm Hg. During long-term infusion of [Sar1,Ala8]angiotensin II (5 microng/kg min-1), PAC averaged 34.7 +/- 8.5 ng/dl, PCC averaged 1.5 +/- 0.5 microng/dl, PRA averaged 16.4 +/- 3.1 ng/ml per hour, and AP averaged 88 +/- 5 mm Hg. During long-term infusion of [Sar1,Ile8]angiotensin II (5 microng/kg min-1), PAC averaged 45.8 +/- 12.6 ng/dl, PCC averaged 1.75 +/- 0.5 microng/dl, PRA averaged 13.6 +/- 4.3 ng/ml per hour, and AP averaged 86 +/- 5 mm Hg. During long-term infusion of angiotensin I-converting enzyme inhibitor (5 microng/kg min-1), PAC averaged 14.9 +/- 4.8 ng/dl, PCC averaged 1.75 +/- 0.5 microng/dl, PRA averaged 20.3 +/- 5.3 ng/ml per hour, and AP averaged 76 +/- 5 mm Hg. The intrinsic agonistic properties of the angiotensin II inhibitory analogues on the adrenal cortex negate their use for defining the role of the renin-angiotensin system in the regulation of aldosterone biosynthesis during sodium deficiency. The precipitous fall in aldosterone secretion and arterial blood pressure during long-term infusion of angiotensin I-converting enzyme inhibitor demonstrates the importance of the renin-angiotensin system in mediating aldosterone biosynthesis during sodium deficiency and the essential role of the renin-angiotensin-aldosterone system in the regulation of arterial pressure during sodium deficiency.

Topics: Aldosterone; Angiotensin II; Animals; Blood Pressure; Diet, Sodium-Restricted; Dogs; Hydrocortisone; Hyponatremia; Potassium; Renin; Saralasin; Sodium; Teprotide

Circulating angiotensin II is said to inhibit renin release by a direct, intrarenal action. This effect of angiotensin was studied indirectly using the selective angiotensin II antagonist saralasin (1Sar-8-Ala-angiotensin II) in conscious normal, sodium-depleted, and sodium-loaded rats. Saralasin caused a dose-related increase in plasma renin concentration (PRC) in normal and sodium-depleted rats, but had no effect on PRC in sodium-loaded animals. However, saralasin was 300 times more active in sodium-depleted rats than in normal rats. Saralasin caused hypotension and tachycardia in sodium-depleted rats, but not in normals. Propranolol inhibited saralasin-induced renin release by 99% in normal rats and by 75% in sodium-depleted rats but not alter the hypotensive effect of saralasin in the latter. Saralasin potentiated phentolamine-induced renin release, hypotension, and tachycardia in normal rats, and this potentiated renin release was blocked by propranolol. We conclude that a portion of saralasin-elicited renin release in sodium-depleted rats is mediated by hypotensive activation of the carotid baroreceptor reflex which increases sympathetic nervous activity in the kidney. However, in sodium-depleted rats saralasin induced a 42-fold increase in PRC, whereas an equipotent hypotensive dose of the vasodilator hydralazine caused only a 3.5-fold increase in PRC. Thus, we find that saralasin appears to have a selective effect on renin release over and above its hypotensive effect, which suggests an angiotensin-mediated, feedback mechanism inhibitory to renin release. Thus, we have come to the conclusion that for part of saralasin-induced renin release appears to be caused by disinhibition of angiotensin suppression of renin secretion. This "short-loop" feed-back mechanism is closely associated with intrarenal beta-adrenergic receptors, since propranolol impaired saralasin-induced renin release under all circumstances in our experiments.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Dose-Response Relationship, Drug; Feedback; Hydralazine; Hyponatremia; Kidney; Kinetics; Male; Propranolol; Rats; Receptors, Adrenergic; Renin; Saralasin; Sodium; Time Factors

Clonidine was nonhypotensive in conscious unrestrained rats maintained on a normal sodium intake. In contradistinction, clonidine caused a dose-related hypotension in conscious unrestrained rats subjected to sodium depletion via furosemide. The plasma renin activity of normal and sodium-depleted rats was reduced after the administration of clonidine (100 mug/kg, iv) by 22.8% and 34.4%, respectively. Intravenous infusion of an angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II, caused a significant reduction of arterial blood pressure in sodium-depleted rats but not in normal rats. Similarly, bilateral nephrectomy reduced arterial blood pressure and completely abolished the hypotensive effect of clonidine in sodium-depleted rats. Subcutaneous administration of chlorisondamine caused a significantly greater reduction of arterial blood pressure in sodium-depleted rats than it did in normal rats. Treatment of normal and sodium-depleted rats with 6-hydroxydopamine reduced the arterial blood pressure of both groups to approximately 85 mm Hg and completely abolished the hypotensive effect of clonidine in the sodium-depleted rats. The data presented in this paper are consistent with the conclusion that clonidine acts at some site in the sympathetic nervous system of sodium-depleted rats to inhibit renal nerve activity with a resultant suppression of renin secretion and a reduction of the angiotensin II-maintained arterial blood pressure. A similar sequence of events occurring in normal rats would not result in hypotension because their arterial blood pressure is not maintained by angiotensin II.

Topics: Animals; Blood Pressure; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Furosemide; Heart Rate; Hydroxydopamines; Hypertension; Hyponatremia; Hypotension; Male; Nephrectomy; Rats; Renin; Saralasin