Short Communication
Drugs 40 (Suppl, 4): 71-72. 1990 00 12-6667/9 0/0 400-0071/$ 1.00/0 © Adis Internat ional Limited All rights reser ved. DRSUP19 36.
substantiall y improve ventilatory function in hypertensive patients with nonasthmatic chronic airway obstruction who were not receiving bronchodilating agents.
1. Patients and Methods
Acute Effects of Urapidil on Airway Response in 'H ypertensive Patients with Chronic Obstructive Pulmonary Disease M . Cazzola, I A. Spinazzi.t G. Santan~elo, I V. W. Steinijans.t W. Wurst, P. Solledert and G. GirbinoI Division of Pneumology and Respiratory Allergy. A. Cardarelli Hospital. Naples, Italy 2 Institute of Pulmonary Medicine. University of Messina. Messina. Italy 3 Byk Gulden Pharmaceuticals, Milan , Ital y and Konstanz, Federal Republic of Germany
The effect of antihypertensive treatment on respiratory function is an important consideration in hypertensive patients with chronic airway obstruction, particulary when the drug used has a prolonged duration of action (Dinh Xuan 1989). Urapidil (Schoetensack et al. 1983) reduces blood pressure through peripheral al-adrenoceptor blockade (Beller et aI.1987; Sanders et al. 1985; Zwieten et aI. 1985) and inhibition of sympathetic counter-regulation via stimulation of central serotonin 1A receptors (Kolassa et al. 1989; Mandai et aI. 1989). Recent pharmacological studies have shown that urapidil inhibits norepinephrine (noradrenaline)and phenylephrine-induced contraction of trachea strips and histamine-induced bronchospasm in spontaneously breathing guinea-pigs (Kilian et al. 1987; Murai et aI. 1988). Wiessman et aI. (1983) observed that intravenous infusions of urapidil 50mg did not affect pulmonary function in hypertensive patients with chronic obstructive pulmonary disease (COPD) who were receiving bronchodilator treatment. This study investigated whether urapidil could
Ten male and 2 female patients (aged 44 to 69 years, height 158 to 175cm, bodyweight 60 to 83kg) with uncomplicated essential hypertension gave their informed consent before inclusion in the study. All patients had COPD,predominantly bronchitis, with a mean forced expiratory volume at I second (FEV d of 68% (41 to 86%) of the predicted value. Exclusion criteria were secondary hypertension , asthma, emphysema, restrictive lung disease, heart disease, pregnancy, breast feeding, and lack of safe contraception in premenopausal women. . The trial was designed as a single-blind randomised 3-period change-over comparison. Each patient was randomly allocated to a sequence of 3 treatments, consisting of intravenous infusion of urapidil 25mg, 50mg and placebo, over 10 minutes ; Three days elapsed between treatments, to avoid carry-over effects and to establish a new baseline on each occasion. Previous antihypertensive therapy, if any, was stopped at least 3 weeks before the start of the study period, and administration of bronchodilator drugs was avoided during the 12 hours ,preceding ,each study session. Xanthine-containing food andbeverages were not allowed, beginning 12 hours before the study period. Spirometry was performed before and 5, 15, 30, 60, 120 and 180 minutes after the start of each of the 3 infusions. Forced expiratory volume manoeuvres were repeated until 2 reproducible results of the forced vital capacity (FVC) and the FEV 1 were obtained. The best .acceptable values of FEV 1 were used for analysis. The forced expiratory flow at 50% of FVC (FEFso) was measured from the manoeuvre with the largest sum of FVC and FEV I. Supine blood pressure and heart rate were also recorded at these times. An ECG was recorded 60 and 180 minutes after each infusion had started.
72
Drugs 40 (Suppl. 4) 1990
Differences in heart rate or airway responses were tested by means of the Friedman test (1% level, 2-sided). A statistical significance of 1% was considered clinically relevant because of the multiple testing at all times of measurement. The blood pressure-lowering effect was tested for dose-dependency by means of the distribution-free Page test (1% level, I-sided).
2. Results Baseline values of all parameters were homogeneous between the 3 study periods. No statistically significant changes in FEV I or FEF50 relative to baseline were recorded after administration of either urapidil or placebo, although urapidil tended to increase both these parameters. An immediate but short lasting increase in mean FEV I was observed after infusion of urapidil25mg; the higher dose produced a greater and more prolonged rise in both FEV I and FEF50. FEV I increased by > 15%and FEF50 by > 25% in 5·and 4 patients, respectively, after administration of urapidil 25mg, and in 7 and 6 patients, respectively, after urapidil 50mg. Similar bronchodilatory effects were not seen after administration of placebo. Urapidil caused a transient increase in heart rate which became statistically significant (p < 0.01) 30 minutes after the start of the infusion. Systolic blood pressure showed a significant (p < 0.01) and dosedependent decrease 5, 15 and 60 minutes after the beginning of infusion with urapidil 25mg or 50mg, whereas the changes in diastolic blood pressure did not reach statistical significance. Neither ECG changes nor adverse reactions were observed.
3. Conclusion Intravenous administration of urapidil did not adversely influence ventilatory function in these patients with hypertension and chronic airflow obstruction. Moreover, in some urapidil recipients,
the drug caused a transient, dose-dependent bronchodilatation. Leonetti et al. (1986), in a study of 40 patients with mild to moderate essential hypertension but normal lung function, reported that urapidil 30mg twice daily for 4 weeks had no effect on FEV I , whereas a significant reduction in FEV I was observed in the same patients after crossing over to the selective {j\-adrenoceptor blocking drug, metoprolol. Therefore, urapidil appears to be a safe and useful blood pressure-lowering agent in hypertensive patients with concomitant COPD.
References Beller K-D. Bischler P, Kolassa N, Sanders KH. Different effects of urapidil and prazosin on blood pressure, heart rate and alphaj-adrenoceptor sensitivity in cats. Journal of Hypertension 5 (SuppI. 5): SI89-S191, 1987 Dinh Xuan AT. Asthme et traitements antihypertenseurs . Revue des Malad ies Respiratoires 6: 295-30 I, 1989 Kilian U, Eltze M, Kolassa N. Interact ion with histam in Hj-receptors and bronchospasmolytic effects of urap idil. Respiration 51: 16-25, 1987 Kolassa N, Beller K-D, Sanders KH. Evidence for the interaction of urapidil with 5-HT' A receptors in the brain leading to a decrease in blood pressure. American Journal of Cardiology 63: 36C-39C, 1989 . Leonetti G, Mazzola C, Boni S, Guffanti E. Meani A. et al. Comparison of the antihypertensive effect of urapidil and metoprolol in hypertension. European Journal of Clinical Pharmacology30: 637-640, 1986 Mandai AK, Kellar KJ, Friedman E, Pineo SV, Hamosh P,et al. Importance of central nervous sy stem serotonin-j A receptors for mediating the hypotensive effect of. urapidil. Journal of Pharmacology and Experimental Therapeutics 251: 563-570, 1989 . . Murai T,iSanai K, Miyao Y, Kanai T. Pharmacological effects of urapidil on bronchospasm, myocardial hypoxia and postural hypotension in experimental animals. Journal of Hypertension 6 (Suppl. 2): S55-S58, 1988 . Sanders KH, Kilian U, Kolassa N, Schoetensack W. Influence of urapidil on alpha- and beta-adrenoreceptors in pithed rats. Journal of Autonomic Pharmacology 5: 307-316, 1985 Schoetensack W, Bruckschen EG, Zech K. Urapidil. In Scriabine (Ed.) New drugs annual: cardiovascular drugs, pp. 19-38, Raven Press, New York, 1983 Van Zwieten PA, de Jonge A, Wilfert B, Timmermanns PB, Beckeringh JJ ,et al. Cardiovascular effects and interaction with adrenoceptors of urapidil, Archives lnternationales de Pharmacodynamie et de Therapie 276: 180-201; 1985 Wiessmann K-J, Munninghoff J,Kruger Ch. Antihypertensive Th erapie mit Urapidil bei Patienten mit ostruktiven Lungenerkrankungen. Fortschritte der Medizin 191: 291.294 , 1983
Correspondence and repr ints: Prof. Dr M. Cazzo/a, Via del Parco Margherita 24, 1-801 21 Napoli , Italy.
Drugs 40 (Suppl, 4): 71-72. 1990 00 12-6667/9 0/0 400-0071/$ 1.00/0 © Adis Internat ional Limited All rights reser ved. DRSUP19 36.
substantiall y improve ventilatory function in hypertensive patients with nonasthmatic chronic airway obstruction who were not receiving bronchodilating agents.
1. Patients and Methods
Acute Effects of Urapidil on Airway Response in 'H ypertensive Patients with Chronic Obstructive Pulmonary Disease M . Cazzola, I A. Spinazzi.t G. Santan~elo, I V. W. Steinijans.t W. Wurst, P. Solledert and G. GirbinoI Division of Pneumology and Respiratory Allergy. A. Cardarelli Hospital. Naples, Italy 2 Institute of Pulmonary Medicine. University of Messina. Messina. Italy 3 Byk Gulden Pharmaceuticals, Milan , Ital y and Konstanz, Federal Republic of Germany
The effect of antihypertensive treatment on respiratory function is an important consideration in hypertensive patients with chronic airway obstruction, particulary when the drug used has a prolonged duration of action (Dinh Xuan 1989). Urapidil (Schoetensack et al. 1983) reduces blood pressure through peripheral al-adrenoceptor blockade (Beller et aI.1987; Sanders et al. 1985; Zwieten et aI. 1985) and inhibition of sympathetic counter-regulation via stimulation of central serotonin 1A receptors (Kolassa et al. 1989; Mandai et aI. 1989). Recent pharmacological studies have shown that urapidil inhibits norepinephrine (noradrenaline)and phenylephrine-induced contraction of trachea strips and histamine-induced bronchospasm in spontaneously breathing guinea-pigs (Kilian et al. 1987; Murai et aI. 1988). Wiessman et aI. (1983) observed that intravenous infusions of urapidil 50mg did not affect pulmonary function in hypertensive patients with chronic obstructive pulmonary disease (COPD) who were receiving bronchodilator treatment. This study investigated whether urapidil could
Ten male and 2 female patients (aged 44 to 69 years, height 158 to 175cm, bodyweight 60 to 83kg) with uncomplicated essential hypertension gave their informed consent before inclusion in the study. All patients had COPD,predominantly bronchitis, with a mean forced expiratory volume at I second (FEV d of 68% (41 to 86%) of the predicted value. Exclusion criteria were secondary hypertension , asthma, emphysema, restrictive lung disease, heart disease, pregnancy, breast feeding, and lack of safe contraception in premenopausal women. . The trial was designed as a single-blind randomised 3-period change-over comparison. Each patient was randomly allocated to a sequence of 3 treatments, consisting of intravenous infusion of urapidil 25mg, 50mg and placebo, over 10 minutes ; Three days elapsed between treatments, to avoid carry-over effects and to establish a new baseline on each occasion. Previous antihypertensive therapy, if any, was stopped at least 3 weeks before the start of the study period, and administration of bronchodilator drugs was avoided during the 12 hours ,preceding ,each study session. Xanthine-containing food andbeverages were not allowed, beginning 12 hours before the study period. Spirometry was performed before and 5, 15, 30, 60, 120 and 180 minutes after the start of each of the 3 infusions. Forced expiratory volume manoeuvres were repeated until 2 reproducible results of the forced vital capacity (FVC) and the FEV 1 were obtained. The best .acceptable values of FEV 1 were used for analysis. The forced expiratory flow at 50% of FVC (FEFso) was measured from the manoeuvre with the largest sum of FVC and FEV I. Supine blood pressure and heart rate were also recorded at these times. An ECG was recorded 60 and 180 minutes after each infusion had started.
72
Drugs 40 (Suppl. 4) 1990
Differences in heart rate or airway responses were tested by means of the Friedman test (1% level, 2-sided). A statistical significance of 1% was considered clinically relevant because of the multiple testing at all times of measurement. The blood pressure-lowering effect was tested for dose-dependency by means of the distribution-free Page test (1% level, I-sided).
2. Results Baseline values of all parameters were homogeneous between the 3 study periods. No statistically significant changes in FEV I or FEF50 relative to baseline were recorded after administration of either urapidil or placebo, although urapidil tended to increase both these parameters. An immediate but short lasting increase in mean FEV I was observed after infusion of urapidil25mg; the higher dose produced a greater and more prolonged rise in both FEV I and FEF50. FEV I increased by > 15%and FEF50 by > 25% in 5·and 4 patients, respectively, after administration of urapidil 25mg, and in 7 and 6 patients, respectively, after urapidil 50mg. Similar bronchodilatory effects were not seen after administration of placebo. Urapidil caused a transient increase in heart rate which became statistically significant (p < 0.01) 30 minutes after the start of the infusion. Systolic blood pressure showed a significant (p < 0.01) and dosedependent decrease 5, 15 and 60 minutes after the beginning of infusion with urapidil 25mg or 50mg, whereas the changes in diastolic blood pressure did not reach statistical significance. Neither ECG changes nor adverse reactions were observed.
3. Conclusion Intravenous administration of urapidil did not adversely influence ventilatory function in these patients with hypertension and chronic airflow obstruction. Moreover, in some urapidil recipients,
the drug caused a transient, dose-dependent bronchodilatation. Leonetti et al. (1986), in a study of 40 patients with mild to moderate essential hypertension but normal lung function, reported that urapidil 30mg twice daily for 4 weeks had no effect on FEV I , whereas a significant reduction in FEV I was observed in the same patients after crossing over to the selective {j\-adrenoceptor blocking drug, metoprolol. Therefore, urapidil appears to be a safe and useful blood pressure-lowering agent in hypertensive patients with concomitant COPD.
References Beller K-D. Bischler P, Kolassa N, Sanders KH. Different effects of urapidil and prazosin on blood pressure, heart rate and alphaj-adrenoceptor sensitivity in cats. Journal of Hypertension 5 (SuppI. 5): SI89-S191, 1987 Dinh Xuan AT. Asthme et traitements antihypertenseurs . Revue des Malad ies Respiratoires 6: 295-30 I, 1989 Kilian U, Eltze M, Kolassa N. Interact ion with histam in Hj-receptors and bronchospasmolytic effects of urap idil. Respiration 51: 16-25, 1987 Kolassa N, Beller K-D, Sanders KH. Evidence for the interaction of urapidil with 5-HT' A receptors in the brain leading to a decrease in blood pressure. American Journal of Cardiology 63: 36C-39C, 1989 . Leonetti G, Mazzola C, Boni S, Guffanti E. Meani A. et al. Comparison of the antihypertensive effect of urapidil and metoprolol in hypertension. European Journal of Clinical Pharmacology30: 637-640, 1986 Mandai AK, Kellar KJ, Friedman E, Pineo SV, Hamosh P,et al. Importance of central nervous sy stem serotonin-j A receptors for mediating the hypotensive effect of. urapidil. Journal of Pharmacology and Experimental Therapeutics 251: 563-570, 1989 . . Murai T,iSanai K, Miyao Y, Kanai T. Pharmacological effects of urapidil on bronchospasm, myocardial hypoxia and postural hypotension in experimental animals. Journal of Hypertension 6 (Suppl. 2): S55-S58, 1988 . Sanders KH, Kilian U, Kolassa N, Schoetensack W. Influence of urapidil on alpha- and beta-adrenoreceptors in pithed rats. Journal of Autonomic Pharmacology 5: 307-316, 1985 Schoetensack W, Bruckschen EG, Zech K. Urapidil. In Scriabine (Ed.) New drugs annual: cardiovascular drugs, pp. 19-38, Raven Press, New York, 1983 Van Zwieten PA, de Jonge A, Wilfert B, Timmermanns PB, Beckeringh JJ ,et al. Cardiovascular effects and interaction with adrenoceptors of urapidil, Archives lnternationales de Pharmacodynamie et de Therapie 276: 180-201; 1985 Wiessmann K-J, Munninghoff J,Kruger Ch. Antihypertensive Th erapie mit Urapidil bei Patienten mit ostruktiven Lungenerkrankungen. Fortschritte der Medizin 191: 291.294 , 1983
Correspondence and repr ints: Prof. Dr M. Cazzo/a, Via del Parco Margherita 24, 1-801 21 Napoli , Italy.
