The effects of captopril on the renin-angiotensin system and the sympathetic nervous system during sodium nitroprusside-induced hypotension in the halothane-anesthetized rabbit.

Three groups of New Zealand white rabbits were used to study the effects of captopril on the renin-angiotensin system and sympathetic nervous system during sodium nitroprusside (SNP)-induced hypotension and halothane anesthesia. Two groups of rabbits (C and CH) were treated with captopril 2 mg/kg i.v. One captopril-treated group (CH) and the third, untreated group (H) received SNP to induce hypotension. In these two groups, the mean arterial blood pressure (MAP) was reduced by 40% for 150 min. Group C did not undergo SNP-induced hypotension and served to document the effects of captopril alone during the 150-min study period. Arterial blood samples for norepinephrine (NE), epinephrine (EPI), and plasma renin activity (PRA) were drawn prior to, during hypotension, and in the recovery period. The SNP dose required to maintain the hypotension was continuously recorded. NE, EPI, and PRA all increased in group H, indicating activation of both the renin-angiotensin system and the sympathetic system during hypotension. This was accompanied by a dramatic increase in SNP dose requirement. In the CH group, PRA levels rose sharply and remained elevated. Plasma NE levels increased, while EPI levels remained unchanged with a decline in the SNP dose requirement. The C group demonstrated a rise in PRA levels, accompanied by unchanged NE and EPI levels and MAP during the study period. Captopril administration decreased the SNP dose requirement and significantly decreased the sympathetic response (measured by NE and EPI levels) in group CH as compared to the H group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Opioids potentiate contractile response of rabbit myocardium to the beta adrenergic agonist isoproterenol.

Opioid agonists and antagonists have both been reported to augment myocardial contractile force in vitro. We reported that the strong opioid agonists morphine and levorphanol, the weak agonist dextrorphan (an optical isomer of levorphanol), and the opioid antagonist naloxone all potentiate the stimulatory effects of the beta-adrenergic agonist isoproterenol on isometric tension generated by isolated rabbit right ventricular myocardium. The EC50 of isoproterenol was found to be shifted leftward 2.7-, 5.4-, 5.3-, and 3.4-fold respectively (p less than 0.05 when compared with controls), when the opioids were added at a final concentration of 1 x 10(5) M. Lower concentrations of opioid or antagonist did not potentiate the effects of isoproterenol. The rank order potency for potentiation thus differs markedly from that of opioid analgesia. The observed potentiation is therefore not agonist specific and not stereospecific. Furthermore, the drugs alone at a range of concentration from 10(-8) to 10(-5) M had no effect on isometric tension generated. We conclude that opioid agonists and antagonists potentiate the response of ventricular myocardium to the effects of beta-adrenergic stimulation by a novel mechanism unrelated to the binding of these drugs to opioid receptors. The paradoxical augmentation of myocardial contractility by either class of agent under a variety of clinical and experimental conditions is thus explained by these findings. Either agent may interact with myocardial tissue to cause increased sensitivity to stimulation by circulating catecholamines.     

Selective reduction of adrenal medulla response to angiotensin induced by suppression of renin-angiotensin.

Angiotensin II (AII) induced an increase of adrenaline (A) release from rat adrenal glands in vitro. The response of the adrenal glands was completely abolished 22--24 h after bilateral nephrectomy. Adrenal glands from DOCA-salt-treated rats did not respond to AII as well, whereas adrenal glands from rats treated with furosemide and a low salt diet retained this response. High potassium in the medium increased significantly the release of A from in vitro incubated adrenal glands of nephrectomized rats from 0.43 +/- 0.04 to 0.63 +/- 0.06 microgram/gland and salbutamol (in calcium-free medium) increased the release from 0.34 +/- 0.03 to 0.43 +/- 0.03 microgram/gland. These results indicate that the adrenal medulla develops subsensitivity to AII in vitro, following a reduction in levels of this agonist in vivo.     

The effects of adrenergic drugs on the rabbit oviduct

This study confirms the presence of α-adrenergic receptors, subserving contraction, and β-adrenergic receptors, subserving relaxation, in both the ampulla and isthmus portions of the oviduct of the anesthetized rabbit. The pressor response to phenylephrine and its contractile responses in the ampulla and isthmus were blocked by phentolamine. The increases in intra-luminal pressure over control levels did not differ significantly between isthmus and ampulla. Propranolol produced a qualitatively similar blockade of the inhibitory effects of isoprenaline on ampulla and isthmus as well as its vasodepressor effect. Angiotensin produced a contractile response in the oviduct that was reduced by phentolamine.     

The potentiating effects of 4-aminopyridine on adrenergic transmission in the rabbit vas deferens.

The effects of 4-aminipyridine on adrenergic transmission in rabbit vas deferens were investigated. 10(-5)-10(-3) M 4-aminopyridine markedly potentiated the sustained, secondary contractile response to transmural stimulation and significantly increased the amount of (+/-)-|3H]-metaraminol released at 5 Hz, but had little effect on responses to exogenous (-)-noradrenaline. 10(-5)-10(-4) M 4-aminopyridine did not significantly alter the accumulation or efflux of (-)-[3H]-noradrenaline in rabbit heart. It is suggested that 4-aminopyridine potentiated responses of rabbit vas deferens to transmural stimulation mainly by increasing transmitter release, possibly as a result of prolongation of the action potential. Responses to transmural stimulation were also potentiated by by 2- and 3-aminopyridine and by 3,4-diaminopyridine but not by pyridine, aniline, 4-dimethylaminopyridine, 4-aminoethylpyridine or 2-aminopyrimidine.     

Modulation by acetylcholine of adrenergic transmission in the rabbit ear artery.

1. Low concentrations of acetylcholine (4 times 10(-11) and 1 times 10(-10) M) increase the vasoconstrictor response of the isolated ear artery of the rabbit to stimulation of the periarterial sympathetic nerves. Higher concentrations (4 times 10(-8) M and greater) decrease the response. 2. Low concentrations of acetylcholine (1 times 10(-11) and 1 times 10(-10) M) increase the stimulation-induced efflux of radioactivity from artery segments previously incubated with [3H]-noradrenaline. Higher ocncentrations (3 times 10(-8) M and greater) decrease the efflux. 3. Neither atropine nor hexamethonium affects the facilitatory action of low concentrations of acetylcholine on adrenergic transmission in the rabbit ear artery. 4. Atropine antagonizes the inhibitory effect of higher concentrations of acetylcholine on adrenergic transmission.     

Some observations on the development of adrenergic innervation in rabbit intestine.

1 Stimulation of periarterial nerves to the ileum of 1 to 12 day old rabbits with supramaximal voltages and frequencies of 1, 2, 5, 10 and 20 Hz with square wave pulses of 2--5 ms duration for 30--40 s produced responses that were initially contractor. In the course of the first week, the responses changed from motor to inhibitory, the change occurring first at the highest rates of stimulation. By the 7th day of life, almost all responses were inhibitory. 2 The motor responses were potentiated by physostigmine and blocked by hyoscine suggesting that they were mediated by acetylcholine. 3 In preparations from rabbits older than 3 days, motor responses could be converted to inhibitory ones by prior exposure to noradrenaline (NA, 1 microgram/ml) for 20 min. This procedure also significantly increased the responses which were already inhibitory. 4 The ability of the ileum to take up NA increased with age. This uptake was blocked by cocaine. 5 The following explanations are possible: (a) changeover from cholinergic to adrenergic transmission in sympathetic fibres; (b) existence of 'parasympathetic' splanchnic nerves or a permanent cholinergic 'sympathetic' component of splanchnic nerves and (c) temporal delay in the development of adrenergic nerves (compared with cholinergic nerves) in the intestine.     

The effects of nifedipine and hydralazine induced hypotension on sympathetic activity

Summary To determine whether inhibition of sympathetic activity is a factor in calcium antagonist induced hypotension, plasma noradrenaline was measured after intravenous infusion of hydralazine (25 mg) and the calcium antagonist nifedipine (4 mg) in 6 hypertensive males. The resultant reduction in mean blood pressure (12.4% and 14.2% respectively) was accompanied by similar increases in heart rate and plasma noradrenaline concentration. These results suggest that calcium slow channel blockade does not inhibit noradrenaline release from sympathetic nerves and that nifedipine induced hypotension is independent of such a mechanism.     

Differential effects of calcium antagonists and Bay K 8644 on contractile responses to exogenous noradrenaline and adrenergic nerve stimulation in the rabbit ear artery.

1. The effects of three calcium antagonists (nifedipine, verapamil, diltiazem) and the calcium agonist Bay K 8644 were compared on contractile responses of similar amplitude elicited by noradrenaline (NA) and electrical nerve stimulation (ENS) in the rabbit isolated ear artery. 2. Contractions induced by both NA (3 x 10(-7) M) and ENS (10 Hz, 10s) were almost exclusively mediated by alpha 1-adrenoceptors, since 10(-7) M prazosin abolished (NA) or almost abolished (ENS) the responses, and prazosin was more than three orders of magnitude more potent than rauwolscine on both types of response. 3. ENS-induced contractions were considerably less inhibited by nifedipine, verapamil and diltiazem than were those elicited by NA. Bay K 8644 enhanced responses to NA more than those to ENS. 4. The inhibitory effect of nifedipine and Ca2+ deprivation on NA-induced contractions decreased with increasing NA concentration. Reduction of the NA response by prazosin or phenoxybenzamine increased the nifedipine inhibition. 5. Reduction of the ENS-induced contractions by prazosin or phenoxybenzamine, or by use of a lower stimulation frequency did not increase the inhibitory effect of nifedipine. 6. In conclusion, the differential effects of the calcium antagonists on NA- and ENS-induced contractions were not related to differences in alpha-adrenoceptor subtype (alpha 1/alpha 2), receptor reserve or response amplitude, but may rather reflect temporal and spatial differences in alpha-adrenoceptor activation between the responses.     

Ridogrel prevents the thromboxane-mediated pressor response and oedema induced by hydrogen peroxide in isolated rabbit lungs.

Perfusion of isolated rabbit lungs with hydrogen peroxide (H2O2, 3 x 10(-5) M) raised the overflow of thromboxane B2 (TXB2) and the perfusion pressure. H2O2 induced oedema formation and endothelial distress, as evidenced by an increased production of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha). Endothelial cell death did not occur since there was no release of lactate dehydrogenase. The thromboxane A2 (TXA2)-synthase inhibitor/receptor antagonist ridogrel (R68070) further enhanced 6-oxo-PGF1 alpha output, while inhibiting TXB2 release. Ridogrel prevented the rise in pulmonary artery pressure and oedema formation. These data indicate that TXA2 is probably involved in the acute pulmonary pressor response and concomitant oedema formation induced by H2O2. In order to assess the functional activity of the pulmonary endothelium, the uptake of 5-hydroxytryptamine (5-HT) was measured before and 15 min after exposure to H2O2. As the H2O2-induced effects were not associated with any change in the uptake of 5-hydroxytryptamine (5-HT), we conclude that the endothelial injury was reversible or that the 5-HT uptake was not sensitive enough to evaluate the integrity of the pulmonary endothelium during oxidant-induced injury.     

Brain renin-angiotensin system modifies the blood pressure response to intracerebroventricular cadmium in rats

In order to elucidate the involvement of the brain renin-angiotensin system (RAS) in cadmium intracerebroventricular (ICV) hypertension, we evaluated the effects of a pretreatment with different drugs: clonidine, an α₂ adrenergic agonist, enalapril and captopril, both ACE inhibitors, and saralasin, a competitive nonselective AT₁ and AT₂ receptor antagonist. We used a rat strain with low levels of kallikrein (LKR) that was more sensitive to ICV cadmium hypertension, compared with normal kallikrein rats (NKRs), the control strain. The interplay between the kallikrein-kinin system and the RAS in the LKR strain caused various hemodynamic alterations, which we believe were the result of elevated RAS activity in these animals. Moreover, we suggest that the defective kallikrein-kinin system in LKR may also cause an alteration in the activation of brain RAS in these animals. The LKR displayed elevated concentrations of plasma AII, hypertrophy of the myocardium, and initial alterations in the renal glomerulotubular system. With the exception of clonidine, all of the other drugs showed greater antihypertensive effects of differing statistical significance in LKR, compared with NKR. Both ACE inhibitors were able to significantly reduce pressor response to cadmium ICV in LKR throughout the experiment, whereas in NKR, they were only able to reduce the hypertensive peak of cadmium. A significant protective effect was also observed in LKR pretreated with saralasin, while no effect was observed in NKR. These findings confirm the presence of brain RAS activation in LKR and its contribution to the central control of pressor response to cadmium ICV.