Holter monitoring of small breed dogs with advanced myxomatous mitral valve disease with and without a history of syncope.

BACKGROUND: Syncope is a transient loss of consciousness occasionally occurring in dogs with advanced myxomatous mitral valve disease (MMVD). OBJECTIVE: (1) To study ECG changes during syncopal episodes in dogs with advanced MMVD and (2) to compare the occurrence of arrhythmias and changes in heart rate variability (HRV) between dogs with advanced MMVD with and without a history of syncope. ANIMALS: Forty-three privately owned dogs (<15 kg) with advanced MMVD: 21 with and 22 without a history of syncope. METHODS: Prospective study with dogs recruited for an evaluation including history, physical examination, echocardiography, and arrhythmia and HRV analysis performed on 24-hour Holter recordings. RESULTS: A syncopal episode was observed during Holter monitoring in 4 dogs: 3 dogs had sinus rhythm and 1 dog had sinus arrest followed by escape rhythm. An arrhythmia variable representing sinus arrhythmia was significantly lower in dogs with a history of syncope than in those without (P = .008). Eight of 26 HRV variables were significantly different between dogs with and without a history of syncope. CONCLUSIONS AND CLINICAL IMPORTANCE: Compared with dogs without a history of syncope, dogs with advanced MMVD and a history of syncope did not have a higher occurrence of arrhythmias, but had less sinus arrhythmia, and had changes in HRV variables representing decreased overall HRV, decreased parasympathetic, and increased sympathetic modulation of heart rate.

Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. OBJECTIVES: To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. ANIMALS: A total of 260 dogs in CHF because of MMVD. METHODS: A prospective single-blinded study with dogs randomized to receive pimobendan (0.4-0.6 mg/kg/day) or benazepril hydrochloride (0.25-1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. RESULTS: A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30-276 days versus benazepril 59 days, IQR 11-121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water.

Radial and longitudinal strain and strain rate assessed by speckle-tracking echocardiography in dogs with myxomatous mitral valve disease.

BACKGROUND: Assessment of left ventricular (LV) function using conventional echocardiographic methods is difficult in mitral regurgitation (MR) owing to altered hemodynamic loading conditions. Newer methods such as speckle-tracking echocardiography (STE) provide assessment of LV strain (St) and strain rates (SR). HYPOTHESES: Global St and SR are 1) decreased in dogs with clinical signs of congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD) compared with clinically healthy dogs, and are 2) associated with conventional echocardiographic indices of MMVD severity. ANIMALS: The study subjects were 93 privately owned dogs with different MMVD severities. METHODS: Prospectively recruited dogs were grouped according to MMVD severity based on echocardiographic evaluation of MR and presence of clinical signs. Global radial and longitudinal St, SR, and indices of LV dyssynchrony were assessed. RESULTS: On group-wise comparisons, dogs with CHF had increased global longitudinal St, global longitudinal and radial SR in systole (SRs), and early diastole (SRe) compared with dogs with no or minimal MR (all P < .04). On multiple regression analyses, these global STE variables increased with degree of MR, but associations with left atrial-to-aortic root ratio (LA/Ao) were best described by second-order polynomial equations. Thus, curvilinear relationships were found for LA/Ao and longitudinal St, SRs, and SRe (all P < .002) and radial St and SRe (all P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Assessed by STE, LV function appeared to be augmented in moderate-to-severe disease. However, at CHF stages with greatly enlarged atria, a decrease to levels comparable to dogs with no or minimal MR was observed.

Heart rate, heart rate variability, and arrhythmias in dogs with myxomatous mitral valve disease.

BACKGROUND: Autonomic modulation of heart rhythm is thought to influence the pathophysiology of myxomatous mitral valve disease (MMVD). HYPOTHESES: (1) Holter-derived variables reflecting autonomic modulation of heart rhythm change with MMVD severity in Cavalier King Charles Spaniels (CKCS); (2) Holter-derived variables can identify MMVD severity in CKCS; and (3) Holter-derived variables in CKCS in congestive heart failure (CHF) secondary to MMVD differ from those in dogs of other breeds in CHF. ANIMALS: Ninety privately owned dogs: 70 CKCS with variable MMVD severity and 20 non-CKCS in CHF secondary to MMVD. METHODS: Dogs were prospectively recruited and divided into 5 MMVD severity groups based on history, breed, and physical and echocardiographic examination findings. Holter-derived variables included heart rate variability (HRV), heart rate (HR), and arrhythmia evaluated from 24-hour Holter recordings. RESULTS: In CKCS, 18 of 26 HRV (all P < .0002) and 3 of 9 arrhythmia (all P < .0004) variables decreased with increasing MMVD, whereas minimum and mean HR (all P < .0001) increased with increasing MMVD severity. An arrhythmia variable representing sinus arrhythmia ("premature normals") (P < .0001) and the HRV variable triangular index (TI) (P < .0001) could distinguish CKCS with moderate or severe mitral regurgitation from CKCS in CHF in specific intervals. Among dogs in CHF, Holter-derived variables did not differ among breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: In CKCS, Holter-derived variables changed with MMVD severity. "Premature normals" and TI showed diagnostic potential. Breed differences were not seen among dogs in CHF secondary to MMVD.

Computed tomographic and magnetic resonance imaging features of canine segmental caudal vena cava aplasia.

OBJECTIVE: To describe the computed tomographic and magnetic resonance imaging features of segmental caudal vena cava aplasia and associated vascular anomalies in dogs. METHODS: A retrospective study was performed reviewing computed tomographic and magnetic resonance imaging archives of eight institutions for dogs with segmental caudal vena cava aplasia. Inclusion criteria included a computed tomographic or magnetic resonance imaging study and supportive diagnostic and follow-up information. Abdominal vessels were reviewed for size, shape, location and course (including tributaries and branches) and classified as normal, abnormal or shunt vessels. RESULTS: Ten dogs with segmental caudal vena cava aplasia were identified. In all dogs, postrenal caval blood was shunted to either a right or a left azygos vein, with seven different angiographic patterns. Affected dogs were predominantly female (70 per cent) and young (mean 2.6 years). Additional portocaval and porto-azygos shunt vessels were identified in two cases each. Computed tomographic angiography and magnetic resonance angiography depicted details of abdominal vessels including thrombus formation in one dog. CLINICAL SIGNIFICANCE: Segmental caudal vena cava aplasia is a vascular congenital anomaly in the dog that can be associated with thrombosis and portosystemic shunts. Computed tomographic angiography and magnetic resonance angiography are excellent tools to demonstrate the complex vascular anatomy and to guide treatment planning for portosystemic shunts and thrombolytic therapy.

Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. HYPOTHESIS: Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. ANIMALS: Two hundred and sixty client-owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. METHODS: A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4-0.6 mg/kg/d) or benazepril hydrochloride (0.25-1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. RESULTS: Eight dogs were excluded from analysis. One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL]=0.516-0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.

Effect of thyroid hormone supplementation on survival of euthyroid dogs with congestive heart failure due to systolic myocardial dysfunction: a double-blind, placebo-controlled trial.

Nineteen euthyroid dogs of 12 breeds with echocardiographic signs of dilated cardiomyopathy (DCM) and radiographic and clinical signs of congestive heart failure (CHF) were evaluated in a randomised, double-blind, and placebo-controlled study. The dogs received either thyroxine or placebo as an adjunct to digoxin, furosemide and propranolol. The group assignment of individual dogs and serum concentrations of thyroid hormones remained unknown to owners and investigators during the entire study period. Dogs were evaluated clinically and with electrocardiography (ECG), thoracic radiography, echocardiography and measurement of total thyroxine (tT4) and thyroid stimulating hormone (TSH) before beginning of the trial, and then one week, 2 months, 6 months and yearly after initial examination, and, when applicable, at the time of euthanasia. End-point of the study was euthanasia (n = 17) due to severe congestive heart failure or sudden death (n = 2). Survival times ranged from 17 to 1030 days (median 187 days) in the placebo group, and from 18 to 1000 days (median 73 days) in the treatment group. There was no statistically significant difference in survival times between the treatment group and the placebo group (p = 0.46). Post mortem and histopathologic examinations revealed the attenuated wavy fiber type of DCM in 11 dogs, and myocardial infarcts, arteriosclerosis and chronic valvular disease in one dog. In conclusion, there was a wide range in survival times of dogs treated with digoxin, furosemide and propranolol. Adding thyroid hormones to the treatment did not significantly influence survival.

The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris.

AIMS: Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. We examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. METHODS AND RESULTS: Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo. CONCLUSIONS: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease.

Postexercise ischemia is associated with increased neuropeptide Y in patients with coronary artery disease.

BACKGROUND: Neurohormones may influence vascular tone both during and after exercise. Neuropeptide Y (NPY), which is costored and released with norepinephrine (NE) during sympathetic activity, is a potent vasoconstrictor with a relatively long half-life. We therefore examined its possible association with the ischemic response to exercise in patients with coronary artery disease. METHODS AND RESULTS: Twenty-nine male patients with effort-induced angina pectoris underwent a symptom-limited exercise test. In addition to conventional ST-segment analysis, we examined ischemia on the basis of heart rate (HR)-adjusted ST-segment changes through calculation of the ST/HR slope during the final 4 minutes of exercise and of the ST/HR recovery loop after exercise. Blood samples were taken before, during, and after exercise for an analysis of several neurohormones. Mean ST-segment depression was -223+/-20.2 microV (P:<0.0001) just before the termination of exercise, followed by a gradual normalization, but it remained significant after 10 minutes (-49+/-8.9 microV, P:<0.0001). At the end of exercise, the ST/HR slope, which reflects myocardial ischemia, was -6.0+/-0.77 microV/HR. In most patients, ST-segment levels at a given HR were lower during recovery than during exercise, here referred to as ST "deficit." Exercise increased the plasma levels of NPY, NE, epinephrine, and N-terminal proatrial natriuretic peptide, but big endothelin remained unchanged. Although NE and epinephrine peaked at maximal exercise, the highest levels of NPY and N-terminal proatrial natriuretic peptide were observed 4 minutes after exercise. The maximal increase in the NPY correlated significantly with ST-segment depression at 3 minutes after exercise (r=-0.61, P:= 0.0005), the ST deficit at the corresponding time point (r=-0.66, P:= 0.0001), and the duration of ST-segment depression after exercise (r= 0.42, P:=0.02). In contrast, no such correlations were found for NE. CONCLUSIONS: The present study has for the first time demonstrated a correlation between plasma NPY levels and the degree and duration of ST-segment depression after exercise in patients with coronary artery disease, which suggests that NPY may contribute to myocardial ischemia in these patients.

Prostacyclin synthesis in relation to sympathoadrenal activation. Effects of beta-blockade.

Results from several studies suggest that beta-adrenoceptor blockade causes increased biosynthesis of the vasodilator prostanoid prostacyclin in the arterial wall. This effect may contribute to the clinical effects of beta-blockers in hypertension and coronary heart disease. Studies in hypertensive patients and in animals indicate that the arterial pressure reduction after beta-blockade is related to the associated increase of prostacyclin biosynthesis, regarding both magnitude and time of onset of effect. Some observations suggest that the effects of beta-blockers in myocardial ischemia may in part be due to an improvement of coronary blood flow caused by increased prostacyclin biosynthesis.

Long-term cardiovascular effects of metoprolol therapy: a review article.

Long-term studies in primary and secondary prevention using metoprolol have showed improvement in prognosis. This review summarizes the clinical results of such studies, and puts these results into the perspective of findings in mechanistic and explanatory studies. Many possible factors may have contributed to explain the beneficial effects on prognosis. The antihypertensive action, cardiac anti-ischemic action, antifibrillatory action, antiatherogenic and antithrombotic actions of metoprolol are discussed. The additive effects of these actions may explain the clinically observed beneficial effects. In the evaluation of a specific intervention, it is important to realize the multiple actions that may contribute, and not only discuss single factors.

Influence of metoprolol CR/ZOK on plasminogen activator inhibitor (PAI-1) in man: a pilot study.

Recent primary and secondary preventive trials have shown that long-term metoprolol therapy reduces the risk of acute cardiovascular complications. To test whether part of this beneficial long-term effect may be due to effects on the fibrinolytic system, three pilot studies were performed; two in healthy individuals, and one in patients with mild hypertension or uncomplicated atrial fibrillation. The effect of metoprolol CR/ZOK (controlled release) 100-200 mg daily, on plasminogen activator inhibitor activity (PAI-1) in plasma was measured. In addition serum triglycerides and orosomucoid were analyzed. All the individuals were included in double-blind placebo controlled cross-over trials with treatment periods ranging from 4 days to 3 weeks. During metoprolol therapy PAI-1 values were reduced, while orosomucoid and triglyceride levels were unchanged. A linear inverse correlation was found between fibrinolysis and PAI-1 activity in plasma, indicating that PAI-1 activity serves as an indicator of fibrinolysis. PAI-1 activity and triglycerides were significantly correlated during placebo and metoprolol therapy. In conclusion, our results in these pilot studies suggest that metoprolol enhances fibrinolytic activity as seen by reduced PAI-1 activity. These results should be further confirmed and put into relation of clinical effects of the therapy.

The role of sympathetic activity in atherogenesis: effects of beta-blockade.

Clinical and experimental evidence points to potential antiatherosclerotic effects of certain beta-adrenoreceptor antagonists. Long-term treatment with metoprolol resulted in significant reductions of total and cardiovascular mortality or morbidity due to decreased incidence of coronary and cerebrovascular complications both in a primary prevention trial in hypertensive patients and in a secondary prevention trial in patients surviving myocardial infarction. The observations suggest that a retardation of atherosclerosis development might have contributed to the reduced incidence of cardiovascular complications. An antiatherosclerotic effect of beta-blockers has been directly demonstrated in animal studies. In cholesterol-fed rabbits, metoprolol significantly reduced the development of atherosclerotic plaques in the aortic intima in the absence of any changes in blood lipids. Similar findings were reported for propranolol, which prevented psychosocial stress-induced atherosclerosis of the coronary artery in monkeys. Furthermore, beta-blockers have been shown to prevent stress-induced endothelial injury and platelet accumulation to intima at atherosclerotic predilection sites in animal models. These antiatherogenic effects may be due to biochemical and hemodynamic factors. Two biochemical effects of beta-blockade may lead to reduced cholesterol accumulation in arterial intima at unchanged serum cholesterol levels. One is a beta-blocker-induced increase of prostacyclin biosynthesis, and the other a metabolic change of low-density lipoprotein, reducing its potential for deposition in the arterial wall. The antiatherogenic effect of these factors may be reinforced by beta-blocker-induced hemodynamic changes leading to reductions of arterial flow aberrations and pressure-related wall stress.

Prejunctional beta 2-adrenoreceptor blockade reduces nerve stimulation evoked release of endogenous noradrenaline in skeletal muscle in situ.

Prejunctional beta-adrenoceptor-mediated modulation of endogenous noradrenaline (NA) overflow elicited by sympathetic nerve stimulation was studied in blood-perfused canine gracilis muscle in situ. An attempt was made to subclassify these beta-adrenoceptors by comparing the effects of beta 1-selective (metoprolol) and non-selective (propranolol) beta-adrenoceptor blockade. Animals were pre-treated with desipramine and phenoxybenzamine in order to counteract possible influences of neuronal uptake and stimulation-evoked changes in vascular resistance on the diffusion of NA into the blood stream. Metoprolol did not decrease stimulation-evoked NA overflow, as compared with control experiments (-10 and -8%, respectively). However, propranolol reduced stimulation-evoked NA overflow by 30% in metoprolol pre-treated animals (P less than 0.05 vs. control experiments). Both antagonists elevated basal perfusion pressure, suggesting that vascular post-junctional beta 1- as well as beta 2-adrenoceptors are present. Propranolol increased stimulation-evoked vasoconstriction in metoprolol pre-treated animals, indicating that neuronally released NA may activate postjunctional beta 2-adrenoceptors under these experimental conditions. In conclusion, our findings suggest that NA release can be enhanced by activation of prejunctional beta 2-adrenoceptors in vivo.

Cardiac anti-ischemic effect of metoprolol: role of beta-blockade within the ischemic region.

The distribution of metoprolol and atenolol into ischemic and nonischemic myocardium was studied in anesthetized dogs, pigs, and cats. The beta-blockers were administered intravenously after coronary artery occlusion. Metoprolol was found to be significantly more efficiently distributed to the ischemic myocardium than atenolol in all three species. To investigate the functional implications of this difference in tissue distribution, the anti-ischemic effects of the two beta-blockers were studied in the 2-h period following coronary artery occlusion in anesthetized cats, in which heart rate was kept at a constant level. In this model, metoprolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) was found to attenuate or delay the developing ischemic process. This is shown by its significant reduction of (a) the decline of CK activity in ischemic myocardium, (b) the ST elevation in a precordial ECG lead, and (c) the decrease of arterial pressure and cardiac output. In contrast to metoprolol, atenolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) caused no significant anti-ischemic effect in this cat model. The difference in the effectiveness of the two drugs can most probably be explained by their differential distribution in the ischemic heart. Furthermore, the anti-ischemic effect of metoprolol shows that the presence of a beta-blocker in ischemic left ventricular myocardium can favorably affect the early phase of developing infarction.

Migraine and beta-blockade: modulation of sympathetic neurotransmission.

The pathophysiology of both classical and common migraine is still not understood, and there is controversy as to whether the origin is vascular, neuronal, or both. Although the mechanism for the prophylactic effect of beta-blockers in migraine has not been elucidated yet, the therapeutic action of beta 1-blockers and non-selective beta-blockers devoid of intrinsic activity is well established by many controlled trials. Mainly on the basis of data from animal experiments, the possible role of central beta-adrenoceptor-mediated mechanisms involved in the control of the activity of noradrenergic neurons will be discussed with reference to migraine.

Effect of prenalterol, a beta-1-adrenoceptor agonist, on renin secretion rate in the anaesthetized dog.

The effects of the beta-1-adrenoceptor agonist, prenalterol, 20 microgram/kg intravenously on renin secretion rate (RSR), renal haemodynamics and sodium excretion were examined in anaesthetized dogs with innervated or denervated kidneys. In dogs with innervated kidneys, prenalterol increased RSR from 1.1 +/- 0.2 to 7.9 +/- 0.1 units X min.-1 X g-1 (P less than 0.01). Prenalterol did not affect mean arterial pressure, renal blood flow, glomerular filtration rate or sodium excretion. Heart rate was increased by 53 +/- 17 beats/min. (P less than 0.01). The increase in RSR produced by prenalterol was independent of intact renal innervation as RSR increased to the same extent in dogs with denervated kidneys. Pretreatment with the beta-1-adrenoceptor antagonist, metoprolol 0.5 mg/kg intravenously, abolished the increase in RSR produced by prenalterol. These findings suggest that prenalterol directly activates renal beta-1-adrenoceptors to increase RSR.

The role of prostaglandins in the alpha- and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation.

The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to low level RNS but decreased the renin release response to high level RNS by 31 +/- 8% (P less than 0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68 +/- 6% P less than 0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37 +/- 14% (P less than 0.05). Phenoxybenzamine (0.6 microgram . kg-1 . min-1), alpha-adrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50 +/- 7% (P less than 0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94 +/- 4% (P less than 0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptors mediated renal vasoconstriction. Prostaglandins are not involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction.

The role of beta-1-adrenoceptors in the renin release response to graded renal sympathetic nerve stimulation.

The contribution of beta-adrenoceptor activation to renin release was examined in anaesthetized dogs using renal nerve stimulation (RNS) at different discharge rates in the presence of i.v. beta-adrenoceptor blockade. The animals were divided into 2 groups, which received either low or high level of RNS, defined by the frequency of stimulation producing decrease in renal blood flow of 5 and 50%, respectively. Low level RNS increased renin release tenfold. The renin release response was almost abolished by 0.5 mg/kg of metoprolol or dl-propranolol but unaffected by 0.5 mg/kg of d-propranolol. The increase in renin release to high level RNS was equally reduced by 33% by 0.5 mg/kg and 2.0 mg/kg of metoprolol. dl-propranolol, 0.5 mg/kg, reduced the renin release response to about the same extent, 44%, while 2.0 mg/kg reduced it somewhat more, 59%. This was probably due to its membrane stabilizing properties as d-propranolol, 2.0 mg/kg and lidocaine 2.0 mg/kg + 0.1 mg x kg-1 x min-1, also reduced the renin release response. These data suggest that the renin release response to low level RNS is almost completely mediated by beta-adrenoceptors which are of the beta-1 subtype. High level RNS results in a renin release, which is only partly mediated by beta-1-adrenoceptors. The remainder is apparently related to other mechanisms activated by high level RNS and is probably a consequence of the associated renal vasoconstriction.