Vasodilatory Beta-blockers Research Articles

Pharmacotherapy of heart failure A.D. 2023. Expert opinion of Working Group on Cardiovascular Pharmacotherapy, Polish Cardiac Society.

Heart failure (HF) remains one of the most common causes of hospitalization and mortality among Polish patients. The position of the Section of Cardiovascular Pharmacotherapy presents the currently applicable options for pharmacological treatment of HF based on the latest European and American guidelines from 2021-2022 in relation to Polish health care conditions. Treatment of HF varies depending on its clinical presentation (acute/chronic) or left ventricular ejection fraction. Initial treatment of symptomatic patients with features of volume overload is based on diuretics, especially loop drugs. Treatment aimed at reducing mortality and hospitalization should include: drugs blocking the renin-angiotensin-aldosterone system (preferably angiotensin receptor antagonist/neprilisin inhibitor, i.e. sacubitril/valsartan, selected beta-blockers (no class effect - options include bisoprolol, metoprolol succinate, or vasodilatory beta-blockers - carvedilol and nebivolol), mineralocorticoid receptor antagonist and sodium-glucose cotransporter type 2 inhibitor (flozin), constituting the 4 pillars of pharmacotherapy. Their effectiveness of the above-mentioned has been confirmed in numerous prospective, randomized trials. The current HF treatment strategy is based on the fastest possible implementation of all four mentioned classes of drugs due to their independent, additive action. It is also important to individualize therapy according to comorbidities, blood pressure, resting heart rate, or presence of arrhythmia. The manuscript emphasizes cardio- and nephroprotective role of flozins in HF therapy, regardless of ejection fraction. We propose practical guidelines for the use of medicines, the profile of adverse reactions, drug interactions, as well as pharmacoeconomic aspects. The principles of treatment with ivabradine, digoxin, vericiguat, iron supplementation or antiplatelet and anticoagulant therapy were also discussed, along with recent novel drugs including omecamtiv mecarbil, tolvaptan or coenzyme Q10 as well as progress in the prevention and treatment of hyperkalemia. Based on the latest recommendations, treatment regimens for different types of HF were discussed.

Therapeutic Role of Beta-blockers in Hypertension: A Pragmatic Reappraisal

Beta-blockers have been used as first-time antihypertensives for decades and such use has also been recommended by guidelines. However, subsequently some meta-analyses questioned this status of beta-blockers by bringing to light their limitation in terms of stroke prevention and their metabolic sideeffects. Following this, several major international hypertension guidelines have removed beta-blockers from the first line of recommended drugs. Some other guidelines, however, have retained them as first-line antihypertensive. Age is an important determinant of choice of antihypertensives and beta-blockers have proven to be very useful in young hypertensives especially if overweight. Amidst these controversies, vasodilatory beta-blockers have emerged with a new promise. They are potent antihypertensives with better reduction of central aortic pressure and a neutral or favorable metabolic profile.

Abstract 20202: Pharmacodynamic Interactions Between Nebivolol and Valsartan in Healthy Volunteers

Introduction: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusions: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.

Abstract 633: Pharmacodynamic Interactions Between Nebivolol and Valsartan in Healthy Volunteers

Background: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusion: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.

Beta-Blockers in the Management of Hypertension and/or Chronic Kidney Disease.

This minireview provides current summaries of beta-blocker use in the management of hypertension and/or chronic kidney disease. Accumulated evidence suggests that atenolol is not sufficiently effective as a primary tool to treat hypertension. The less-than-adequate effect of beta-blockers in lowering the blood pressure and on vascular protection, and the unfavorable effects of these drugs, as compared to other antihypertensive agents, on the metabolic profile have been pointed out. On the other hand, in patients with chronic kidney disease, renin-angiotensin system blockers are the drugs of first choice for achieving the goal of renal protection. Recent studies have reported that vasodilatory beta-blockers have adequate antihypertensive efficacy and less harmful effects on the metabolic profile, and also exert beneficial effects on endothelial function and renal protection. However, there is still not sufficient evidence on the beneficial effects of the new beta-blockers.

Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats.

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.

Pulmonary vasoconstrictor responses

Alterations in the physiological balance to maintain the pulmonary circulation at a normal low pressure level result in an elevation in pulmonary vascular tone. Pulmonary vasoconstrictor responses were analyzed under some experimental conditions, which included microembolism, administration of vasoactive agents, hypoxia, and monocrotaline-induced pulmonary hypertension. It is widely accepted that these responses are highly localized and complex. In the present study, excised canine lung lobes, rat lungs, and pulmonary arterial rings from the rat were employed according to the particular experimental design. The mechanism of the initial rapid elevation followed by a gradual decline in perfusion pressure in microembolism was considered to be related not only to the size of the emboli, but to the degree of mechanical injury of the endothelium. The main sites of constriction of the pulmonary vasculature by several drugs were determined in the pulsatile perfused canine lung lobes, according to the degree of decrease in inflow wave amplitude during antegrade or retrograde perfusion. Further, by applying the same method it was confirmed that the site of hypoxic vasoconstriction is located in the peripheral pulmonary vascular bed between the muscular arteries and veins, which are constricted mainly by serotonin and histamine, respectively. A cross perfusion system was set up, employing two lobes from the same dog, in which normoxic blood was perfused into the hypoxic ventilated lobe and vice versa. As a result, the pulmonary vessels showed a response to ventilation hypoxia that was far more sensitive than that to perfusion hypoxia. The effects of a beta-agonist (isoproterenol) and beta-antagonists (propranolol, pindolol) on hypoxic vasoconstriction were observed. Although pindolol (a vasodilatory beta-blocker) abolished hypoxic pulmonary vasoconstriction, which was similar to the effect of isoproterenol, the mechanism of action of pindolol was suggested to be different from that of isoproterenol. The importance of the K+ channel of vascular smooth muscle and also the endothelium in hypoxic pulmonary vasoconstriction were stressed. In isolated pulmonary artery segments of the monocrotaline-treated rat, the augmentation of sensitivity of the vascular smooth muscle to Ca2+ preceded the occurrence of pulmonary hypertension. Similarly, hyperreactivity to KCl and serotonin was also observed. It was clarified that the hyperreactivity induced by monocrotaline is modified by endothelium-dependent relaxation. Extensive cellular and molecular biological investigations are essential for further progress in this field.

Proteomic profiling during atherosclerosis progression: Effect of nebivolol treatment

There is a great need for the identification of biomarkers for the early diagnosis of atherosclerosis and the agents to prevent its progression. The aim of this study was to explore the effect of 24 week of nebivolol (a third-generation vasodilatory beta-blocker) treatment on serum protein profiles in Apo E(-/-) mice during atherosclerosis progression. Nebivolol treated and non-treated (the control group) groups consisted of 10 genetically modified homozygous Apo E(-/-) mice. Proteomic analyses were performed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) in the serum samples from the nebivolol treated and non-treated Apo E(-/-) mice. The protein profiles obtained using three different chips, CM10 (weak cation-exchange), H50 (reverse phase), and IMAC30-Cu(2+) (immobilized metal affinity capture) were statistically analyzed using the ProteinChip data manager 3.0 program. At the end of 24 week of nebivolol-treatment period, a total of 662 protein/peptide clustering peaks were detected using 12 different conditions and reading with high and low intensity laser energy. The highest total number of protein/peptide clusters was found on H50 chip array. The peak intensities of 95 of the 662 protein/peptide clusters were significantly different in the nebivolol-treated atherosclerotic group in comparison to the non-treated control mice groups (P < 0.05). Forty-three protein/peptides were up-regulated (high signal intensity) while 52 protein/peptides had lower signal intensity (down-regulated) in the nebivolol-treated atherosclerotic group. The proteomic profiles of nebivolol-treated Apo E(-/-) mice were different than the control group indicating a potential role of nebivolol in atherosclerosis. Our study contributes to understand the efficacy of nebivolol on serum protein/peptide profiles during atherosclerosis development.

Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction

Cardiovascular disease is the leading cause of death worldwide. Within the treatment armamentarium, beta-blockers have demonstrated efficacy across the spectrum of cardiovascular disease--from modification of a risk factor (ie, hypertension) to treatment after an acute event (ie, myocardial infarction). Recently, the use of beta-blockers as a first-line therapy in hypertension has been called into question. Moreover, beta-blockers as a class are saddled with a misperception of having poor tolerability. However, vasodilatory beta-blockers such as carvedilol have a different hemodynamic action that provides the benefits of beta-blockade with the addition of vasodilation resulting from alpha 1-adrenergic receptor blockade. Vasodilation reduces total peripheral resistance, which may produce an overall positive effect on tolerability. Recently, a new, controlled-release carvedilol formulation has been developed that provides the clinical efficacy of carvedilol but is indicated for once-daily dosing. This review presents an overview of the clinical and pharmacologic carvedilol controlled-release data.

The Changing Landscape of Hypertension and the Evolving Role of Vasodilatory Beta-Blockers

The Changing Landscape of Hypertension and the Evolving Role of Vasodilatory Beta-Blockers

Hypertension and insulin disorders.

Insulin resistance and/or compensatory hyperinsulinemia are associated with hypertension, obesity, dyslipidemia, and glucose intolerance. Insulin resistance and hyperinsulinemia are considered to increase blood pressure through sympathetic nervous system activation, renin-angiotensin system stimulation, and vascular smooth muscle cell proliferation. Leptin, magnesium ions, nitric oxide, endothelin, peroxisome proliferator-activated receptor gamma, and tumor necrosis factor-alpha also modulate blood pressure. Decreasing insulin resistance by lifestyle modification including diet, weight loss, and physical exercise has been shown to reduce blood pressure. Angiotensin-converting enzyme inhibitors have a beneficial effect on insulin resistance. On the other hand, the angiotensin II antagonist, losartan, does not affect insulin sensitivity. The selective alpha1-blockers have a favorable metabolic profile producing increases in insulin sensitivity. A short-acting type calcium channel blocker seems to decrease insulin sensitivity. On the other hand, long-acting type calcium channel blockers improve insulin sensitivity. Thiazide diuretics and most of the beta-blockers decrease insulin sensitivity. Vasodilatory beta-blockers have been reported to improve insulin sensitivity. Use of low-dose diuretics avoids the adverse effects seen with conventional doses.

Effect of vasodilatory beta-adrenoceptor blockers on cardiovascular haemodynamics in anaesthetized rats.

1. The effect of vasodilatory beta-adrenoceptor blockers on regional blood flow in the major organs of anaesthetized rats was investigated using radioactive microspheres. The administration of propranolol and saline was used as a control. 2. Intravenous injections of carvedilol (2 mg/rat), celiprolol (20 mg/rat) and bopindolol (1 mg/rat) equally decreased systemic blood pressure (SBP) by approximately 20 mmHg, whereas propranolol (1 mg/rat) decreased SBP only slightly but not significantly. 3. Heart rate was significantly decreased by carvedilol, celiprolol, bopindolol and propranolol. 4. Coronary blood flow was markedly increased by carvedilol, but not by the other three drugs. 5. Cardiac output tended to decrease following the administration of all four drugs. 6. Total peripheral vascular resistance was not significantly affected by carvedilol, celiprolol and bopindolol, but was markedly increased following propranolol. 7. Renal blood flow was markedly increased by carvedilol. 8. Blood flow in the brown fat was markedly increased by carvedilol and bopindolol, but not by celiprolol and propranolol. 9. These findings indicate that the newer vasodilatory beta-blockers, such as carvedilol and bopindolol, have a beneficial effect on the regional circulation in contrast with the classical beta-blocker propranolol. 10. The regional haemodynamic effects observed in the present study following intravenous injection of the beta-blockers may help explain the clinical experience that vasodilatory beta-blockers increase insulin sensitivity and decrease mortality in patients with congestive heart failure.

Required beta blocker profile in the elderly.

In the truly elderly, a complex balance between compensatory processes and impaired organ function allows reasonably normal physical function. It is argued that beta blockade should have certain desirable qualities to minimize any impairment of organ function, thereby upsetting the quality of life. Thus a simple pharmacokinetic pattern without hepatic metabolism is less likely to cause unexpected variation in blood levels of the beta blocking agents and to have fewer risks of interactions with other drugs including nicotine. Renal-excreted beta blockers--such as atenolol, nadolol, and celiprolol--do, however, need downward dose adjustment when the glomerular filtration rates fall. The elderly are frequently categorized as having a low renin profile, which in the view of some workers may make a vasodilatory beta blocker more desirable. Hemodynamic advantages of such agents include the prime site of attack in hypertension on the increased peripheral vascular resistance, increasingly fundamental with a prolonged duration of hypertension and therefore with the aging process. Furthermore, a normal heart rate with a sustained cardiac output may avoid symptomatic bradycardia. In the elderly, respiratory function may be impaired so that loss of elastic recoil causes elderly emphysema. A highly cardioselective beta blocker should be an advantage. Finally, minimal interference with glucose and lipid metabolism should also be desirable goals.

Effect of Carvedilol on Ambulatory Blood Pressure, Renal Hemodynamics, and Cardiac Function in Essential Hypertension

A randomized, double-blind, placebo-controlled study was set up to study the effects of acute and chronic administration of carvedilol, a vasodilatory beta-blocker in essential hypertension. Acute administration of a single dose of 50 mg of carvedilol reduced systolic and diastolic blood pressure, without inducing reflex tachycardia. Renal blood flow was preserved; accordingly renal vascular resistance was significantly reduced. A significant reduction of glomerular filtration rate and filtration fraction was observed. Plasma renin activity (PRA) and plasma aldosterone were not changed. Chronic carvedilol treatment produced a significant fall in systolic and diastolic office and ambulatory blood pressure, heart rate, cardiac output, PRA and plasma aldosterone. Blood pressure variability was not changed. Renal blood flow, glomerular filtration rate and filtration fraction also remained unchanged; renal vascular resistance decreased significantly. It is concluded that carvedilol possesses definite antihypertensive and renal vasodilating properties, both acutely and after chronic treatment.