Intravenous Administration Of Captopril Research Articles

The effects of two types of renin-angiotensin system inhibitors on the hypertension induced by new pressor protein associated with beta-factor XIIa in rats.

Background and purpose:New pressor protein (NPP) is a human plasma enzyme, which is structurally related to the beta-fragment of activated factor XII. The present study aimed to compare the effects of angiotensin converting enzyme inhibitors (captopril) and angiotensin type 1 receptor blocker (losartan) on the hypertension induced by NPP injection in normal (sham-2NX) and bilaterally nephrectomized rats (2NX).Experimental approach:In total, 60 male Wistar rats were sham operated or bilaterally nephrectomized under anesthesia. After 24 h of anesthesia with Inactin® (100 mg/kg), their systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured before and after the intravenous administration of captopril, losartan, and NPP.Findings / Results:In the sham-2NX group, after NPP injection, changes were observed in SBP (145.99 ± 3.6 mmHg), DBP (93.9 ± 3.87 mmHg), and HR (400.29 ± 12.78 bpm). In the captopril group, SBP and DBP had no significant changes, while HR increased significantly (P = 0.001). In the losartan group, SBP and DBP decreased (P = 0.001 and P = 0.000, respectively), while HR had no significant changes. In the 2NX group, after NPP injection, changes were denoted in SBP (127.89 ± 9.03 mmHg), DBP (65.86 ± 5.69 mmHg), and HR (333.35 ± 11.47 bpm). In addition, captopril injection increased DBP (P = 0.016) and HR (P = 0.036) in response to NPP injection, while losartan injection had no significant effects in this regard.Conclusion and implications:It could be concluded that losartan could improve hypertension in normal rats, while captopril deteriorated hypertension in bilaterally nephrectomized rats in this hypertension model.

Effects of a reversible 'nephrectomy' on renal sympathetic activity and blood pressure in the rat: evidence for an acute angiotensin-mediated hypertension.

To verify whether the normal kidney exerts a supportive, facilitatory action on renal sympathetic nerve activity (RSNA), the effects of unilateral and bilateral nephrectomy on RSNA have been studied. The RSNA, rectal temperature (T), rate of breathing (RB), arterial blood pressure (BP) and heart rate (HR) were continuously recorded in three groups of pentobarbital anaesthetized, spontaneously breathing Sprague-Dawley rats: group 1 (n = 5): both kidneys intact; group 2 (n = 5): left surgical nephrectomy; group 3 (n = 5): left surgical nephrectomy and functional exclusion of the right kidney (functional right nephrectomy, FRN), produced by a tight ligature of the renal hilum which was maintained for 3 h. In a fourth group (n = 7), in which nerve activity was not recorded, reopening of the right renal hilum was preceded or followed by intravenous administration of captopril (3 mg/kg). In groups 1 and 2 RSNA increased from 22.3 +/- 2.1 to 122.9 +/- 13.6 and from 26.7 +/- 1.2 to 93.2 +/- 14.0 impulses/s (mean +/- SEM), respectively, without concomitant changes in cardiovascular parameters. In group 3 RSNA decreased from 39.1 +/- 3.1 to 13.7 +/- 2.6 impulses/s during the 3 h of FRN. In group 3 the reopening of the right renal hilum was followed by a marked increase in BP and HR that was prevented or reversed by intravenous captopril in rats of group 4. The decrease in RSNA observed in rats during bilateral nephrectomy, in contrast to the increase observed in rats with one or both kidneys intact, suggests that the kidney as a whole exerts a supportive role on sympathetic nerve activity. The hypertension and tachycardia that follows the reopening of the right kidney hilum appears to be caused by the generation of endogenous angiotensin II; this is the first evidence of an acute angiotensin-mediated renal hypertension.

Direct effects in vivo of angiotensins I and II on the canine sinus node

The chronotropic responses to angiotensins I and II (5 micrograms in 1 mL Tyrode's solution) injected into the sinus node artery were assessed before and after the intravenous administration of captopril (2 mg/kg) and saralasin (20 micrograms/kg) in anaesthetized dogs. The effects of angiotensin II given intravenously were also observed. The animals (n = 8) were vagotomized and pretreated with propranolol (1 mg/kg, i.v.) to prevent baroreceptor-mediated responses to increases in blood pressure. Injection of angiotensin I into the sinus node artery induced significant increases in heart rate (114 +/- 6 vs. 133 +/- 6 beats/min) and in systemic systolic (134 +/- 13 vs. 157 +/- 14 mmHg; 1 mmHg = 133.3 Pa) and diastolic (95 +/- 10 vs. 126 +/- 13 mmHg) blood pressures. Similar results were obtained when angiotensin II was injected into the sinus node artery, but intravenous injection induced changes in systolic (138 +/- 8 vs. 180 +/- 25 mmHg) and diastolic (103 +/- 8 vs. 145 +/- 20 mmHg) blood pressures only. Captopril induced a significant decrease in systolic (118 +/- 11 vs. 88 +/- 12 mmHg) and diastolic (84 +/- 9 vs. 59 +/- 9 mmHg) blood pressures without affecting the heart rate (109 +/- 6 vs. 106 +/- 6 beats/min). Saralasin produced a significant increase in systolic (109 +/- 7 vs. 126 +/- 12 mmHg) blood pressure only. Increments in heart rate and systolic and diastolic blood pressures in response to angiotensins I and II were, respectively, abolished by captopril and saralasin. It was concluded that angiotensin II has, in vivo, a direct positive chronotropic effect that can be blocked by saralasin.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo comparison of renal and femoral vascular sensitivity and local angiotensin generation.

Experiments were conducted to compare the relative importance of the local renin-angiotensin systems in the rabbit renal and femoral vascular beds and their functional role in hemodynamic regulation. Angiotensin I (Ang I) (0.15 microgram/kg i.v.) elevated mean arterial blood pressure by 18 +/- 1 mm Hg in the renal experimental group and 19 +/- 1 mm Hg in the femoral experimental group; it decreased renal blood flow by 35 +/- 3% but increased femoral blood flow by 31 +/- 8%. All these effects were blocked by intravenous administration of captopril (2 mg/kg bolus injection plus 1 mg/kg/hr). Captopril also lowered mean arterial pressure by 17 +/- 3 and 16 +/- 2 mm Hg in the renal and femoral experimental groups, respectively, and it increased renal blood flow by 32 +/- 10% but reduced femoral blood flow by 21 +/- 4%. As a result, renal vascular resistance was decreased by 36 +/- 5%, but femoral vascular resistance remained unchanged. After captopril, plasma angiotensin II (Ang II) levels were decreased and Ang I levels increased in the two groups. The renal venous-arterial difference of Ang I was increased by captopril, but the femoral venous-arterial difference of Ang I was not, suggesting greater generation of Ang I in the kidney. In a separate group of bilateral nephrectomized rabbits, plasma Ang II levels as well as mean arterial pressure, femoral blood flow, and femoral vascular resistance were not changed by intravenous administration of captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Vasodilator Drugs on Coronary Occlusion and Reperfusion Arrhythmias in Anesthetized Dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.

No Role for Prostaglandins and Bradykinin in the Autoregulation of Renal Blood Flow

In order to evaluate the participation of prostaglandins and bradykinin in autoregulation of renal blood flow, the pressure-flow relationships were examined before and during the infusion of prostaglandin E2, sodium arachidonate or bradykinin in the pump-perfused kidney of anesthetized dogs. Renal arterial pressure was changed in a step-wise fashion between 60 and 200 mmHg by means of a pneumatic resistance. Renal blood flow revealed an effective autoregulation against the pressure changes between 100 and 200 mmHg. Infusion of prostaglandin E2 (30 and 100 ng/min), sodium arachidonate (200 and 500 micrograms/min) or bradykinin (100 and 300 ng/min) into the renal artery increased renal blood flow dose-dependently, but had no influence on the autoregulation of renal blood flow. We also examined the effect of endogenous bradykinin and prostaglandins by the intravenous administration of captopril (1 mg/kg), a kininase II inhibitor, and indomethacin (2.5 mg/kg), a cyclo-oxygenase inhibitor, respectively. Captopril increased renal blood flow, but did not impair the autoregulation. Indomethacin decreased renal blood flow and had no effect on the renal autoregulation. It is considered that prostaglandins and bradykinin which induced renal vasodilation have no role in the autoregulation of renal blood flow in the dog kidney.

Cerebrovascular aspects of converting-enzyme inhibition I: Effects of intravenous captopril in spontaneously hypertensive and normotensive rats.

The cerebrovascular effects of converting enzyme inhibition were examined in normotensive and hypertensive rats. Cerebral blood flow was measured using the intracarotid 133xenon injection method in halothane/nitrous oxide anaesthetized animals. The main finding was that following intravenous administration of captopril (10 mg/kg), cerebral blood flow autoregulation was markedly altered. Although cerebral blood flow was unchanged from baseline levels, both the lower and upper limits of autoregulation were reset to lower mean arterial pressure and the autoregulatory plateau shortened. The lower limit was shifted 20-30 mmHg, the upper limit 50-60 mmHg, and the plateau shortened by 20-40 mmHg. The effect was interpreted as being a consequence of compensatory autoregulatory constriction of small resistance vessels in the brain following captopril-induced dilatation of large resistance vessels. It was inferred that locally produced angiotensin II might play a role in the resistance of large cerebral arteries.

Potentiation of depressor responses to arachidonic acid by angiotensin converting enzyme inhibitors in the rat.

In chloralose anaesthetized rats, intravenous administration of captopril, SQ 20881, SA 446 or MK 421 (0.5 mg/kg) potentiated the depressor responses to arachidonic acid 3 mg/kg given intravenously. Same doses of the above angiotensin converting enzyme inhibitors caused an approximately 100-fold decrease in sensitivity to the pressor effects of angiotensin I, with a concomitant similar increase in sensitivity to the depressor effects of bradykinin. Depressor responses to arachidonic acid, both before and after administering the converting enzyme inhibitors, were abolished by intravenous indomethacin (5 mg/kg). These results suggest that increased synthesis of prostaglandins in the circulation may contribute to the hypotensive effect of the angiotensin converting enzyme inhibitors, a group of newly developed antihypertensive agents.

Converting Enzyme Inhibition and Autoregulation of Cerebral Blood Flow in Spontaneously Hypertensive and Normotensive Rats.

The cerebrovascular effects of the converting enzyme inhibitor captopril were examined after intravenous or intra-cerebroventricular administration in nornotensive and hypertensive rats. Cerebral blood flow (CBF) was measured using the intracarotid 133xenom method in halothane/nitrous oxide anaesthetised animals. Captopril given either way did not influence the absolute value of CBF. The main finding, however, was that following intravenous administration of captopril at a dose af 10 mg/kg, both the lower pressure limit of CBF autoregulation were shifted to lower pressure and the autoregulatory plateau shortened. The lower limit was shifted 20-30 mm Hg, the upper limit 50-60 mm Hg, andthr autoregulatory plateau consequently shortened by 20-30 mm Hg. In contrast to the marked effects of intrvenous captopril, intracerebroventricular captopril was without effect on CBF autoreguletion. The effect of intravenous captopril was thus probably mediatedby converting enzyme in the cerebrovascular endothelium.

ATTENUATION BY CAPTOPRIL OF PRESSOR RESPONSES TO PERIPHERAL SYMPATHETIC NERVE STIMULATION IN RATS IS ABOLISHED AFTER BILATERAL NEPHRECTOMY AND DURING MINERALOCORTICOID HYPERTENSION

Intravenous administration of captopril (0.1-0.3 mg/kg) to normotensive pithed rats, with or without unilateral nephrectomy, was followed by a sustained fall in arterial blood pressure. Concomitantly pressor responses to electrical stimulation of the spinal sympathetic outflow (T11-L3), ganglion stimulation with McNeil-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride) or intravenous injection of noradrenaline were reduced. Attenuation by captopril (1 mg/kg) of pressor responses to McNeil-A-343 persisted after intravenous propranolol (1 mg/kg). Tachycardia caused by electrical stimulation of the spinal sympathetic nerves (C7-T2) was unchanged after 3.0 mg/kg captopril. After procedures reducing the activity of the renin angiotensin system, bilateral nephrectomy or induction of mineralocorticoid hypertension by unilateral nephrectomy and administration of desoxycorticosterone acetate, pressor responses to McNeil-A-343 or noradrenaline were unchanged after 1 mg/kg captopril. It is concluded that in the pithed rat, basal arterial blood pressure and the height of pressor responses to either postganglionic sympathetic nerve activation or intravenous noradrenaline depend on converting enzyme activity maintaining circulating angiotensin II levels.

Cardiovascular responses of conscious doca-salt hypertensive rats to acute intracerebroventricular and intravenous administration of captopril

The effect on blood pressure and heart rate, following administration of the same intracerebroventricular (ivt) and intravenous (iv) doses of captopril, was compared in freely moving DOCA-salt hypertensive rats, with chronically implanted ivt, iv and intraarterial cannulae. Ivt captopril (500 micrograms) in DOCA-salt rats showed an initial pressor response followed by a long lasting hypotensive effect. The ivt effect was greater than that following iv administration. No effect was observed in normotensive controls either ivt or iv. ASA or naloxone pretreatments significantly lowered the captopril hypotensive effect, thus suggesting an involvement of prostaglandin and opioid systems in blood pressure elevation in "non renin dependent" hypertension.

Captopril potentiates depressor responses to arachidonic acid in the rat.

1. In chloralose anaesthetized rats intravenous administration of captopril (0.5 mg/kg) was followed by an approximately 100-fold decrease in sensitivity to the pressor actions of angiotensin I. Concomitantly there was a 100-fold increase in sensitivity to the depressor effects of bradykinin. 2. Depressor responses to intravenous prostacyclin (PGI2), prostaglandin E2 (PGE2) or a low dose of arachidonic acid (1 mg/kg) were not changed by captopril administration, but responses to a high dose of arachidonic acid (3 mg/kg), given either intravenously or into the aortic arch, were enhanced for up to two hours afterwards. 3. Depressor responses to arachidonic acid, both before and after captopril, were inhibited after intravenous indomethacin (1 mg/kg). 4. These results support the hypothesis that increased synthesis of prostaglandins in the circulation contributes to the hypotensive action of captopril.

The role of brain angiotensin II in the mechanism of the pressor responses to intracisternal injection of hypertonic NaCl in urethane anesthetized rats.

Intracisternal injections of hypertonic NaCl elicited the pressor responses in urethane anesthetized spontaneously hypertensive and normotensive Wistar rats. The intracisternal pretreatment of 1-Sar-8-Ile-angiotensin II, angiotensin II analog, could abolish the pressor responses to intracisternal injections of 5% NaCl in urethane anesthetized spontaneously hypertensive rats, while basal blood pressure was not affected by these pretreatment. Both intracisternal and intravenous administration of captopril, an angiotensin I converting enzyme inhibitor, did not alter the pressor effect of hypertonic NaCl in normotensive rats. Basal blood pressure was lowered by intravenous injection of captopril. The involvement of angiotensin II in the pressor mechanism of hypertonic NaCl was confirmed by the enhanced pressor responses to intracisternal injections of 5% NaCl in urethane anesthetized rats pretreated intracisternally with angiotensin II. These findings suggest that angiotensin II itself could play an important role in the pressor responses to intracisternal injections of hypertonic NaCl without involving a converting enzyme system.