- Email: [email protected]
Chapter 6. Antihypertensive Agents
53
Section I1 Editor:
-
Pharmacodynamic Agents
Barry Bloom, Chas. Pfizer & Co., Chapter
Inc., Groton, Conn.
6. Antihypertensive Agents
John G. Topliss, Schering Corporation, Bloomfield, N. J.
-
Catapresan@ Additional papers have appeared in the clinical literature during 1967 on this new antihypertensive agent, but little came forth in the way of new devel- 7 opments concerning- mechanietic aspects of its action. N-1
i'
In one study in rats, evidence was obtained that at least part f the hypotensive action of Catsoresan6 (I) is due -t o a-adrenergic b1ockade.l The infusion I of low doses ( 0 . 2 5 2.0 Pg/kg) into the HC1 cerebral artery of anesthetized cats resulted in a considerable, dose-dependent decrease in blood pressure which developed suddenly,towards the end of the infusion. The same low doses, when given intravenously, had little effect on blood pressure. These results were viewed 88 consistent with a central mechanism of action of the drug. 2
-
An investigation in 21 patients3 produced overall results similar to those obtained previously by other investigators. 4 Wkth a daily dose of about 5007, there was an effective fall in systolic and diastolic blood pressure. Only a slight effect on orthostatic blood pressure was observed, and there was some slowing of the pulse rate. Sedation and dryness of the mouth were noted but were much reduced as the treatment progressed. The urinary excretion o f vanilmandelic acid, the main metabolite of catecholamines, was significantly reduced on the second day of drug administration,as compared to controls. This could have been due to interference with either the synthesis or the secretion of catecholamines. The authors spggested that this observation, coupled with the initial sedative effect and the disturbed sleep of some patients, may indicate a central effect. Another trial was conducted with 25 hypertensive patients over several weeks where the desired lowering of blood pressure was attained on the fourth day of treatment. Side effects were not troublesome.: Renal hypertension may even respond t o easurable degree. Parenteral adminietration of' Catapreea eaems to be eJfective and reliable in the treatment of hyperteneive crises. When combined with a thiazide for chronic administra-
w
54
Sect. I1
-
Pnarmacodynamic Agents
Bloom, Ed.
tion, the antihypertensive effect i s equivalent to thiazide plus a-methyldopa.' In a clinical pharmacologic trial with 12 chronic schizophrenic patients, no antipsychotic activity was observed.'
-
In a series of 25 derivatives of benzylGuanethidine Analogs guanidine, the most active compounds were p-trifluoromethylbenzylguanidine sulfate (11, R = H) and its a-methyl analog (11, R = CH3). NH Oral doses of 30 mg/kg of the former II initially increased, but subsequently pNHcNH2 decreased, blood pressure in both reR nal and neurogenic hypertensive dogs. Blood pressure was reduced for at I1 *1/2H~S04 least 5 0 hr, and the more marked reduction was observed with neurogenic hypertensive dogs. In the case of I1 (R = CH3), doses of 10, 5 and 2.5 mg/kg were employed, and a good dose-response relationship was apparent. Again,the neurogenic dogs exhibited a better response than did the renallo dogs. This compound was notable f o r its lack of side effects. Results of a study of 70 hypertensive patients treated with bethanidine for periods ranging from six months to two years have been reported. Satisfactory control of blood pressure was obtained in about three-quarters of the group, and side effects, apart fxpm postural hypotension (38$ of the patients), were rare. Liver-function test abnormalities have been noted among patients treated with guanoxan.12 The progress of 224 hypertensive patients treated with guanethidine for one to five and one-half years has been assessed .I3 a-Meth 1 Do a +a Related Compounds - It has been shown by Varma & that a-methyldopa produces its usual antihypertensive effect in immuno-sympathectomized rats made hypertensive by metacorticoid treatment. This observation was considered to be inconsistent with the hypothesis of Day and Rand that amethyldopa produces its antihypertensive effect by substituting a less active "false transmitter substance" for noradrenaline in the sympathetic nervous system. However, the latter authors have presented arguments to suggest that despite these findings the false transmitter hypothesis explainfgg the antihypertensive effect of a-methyldopa is still tenable. The proposal that a central effect might be the cause of the decrease of peripheral resistance brought about by amethyldopa is supported by evidence that a central$% mediated hypotensive effect may be demonstrated in the cat.
Chap. 6
Antihypertensives
55 -
Topli s s
A number of observations have been made on the occcrrence of positive Coombs tests and hemolytic anemia in patients receiving a-methyldopa.17-20 In this connection, the nature of the a-methyldopa red-cell antibody has been investigated .20
The antihypertensive2fffects of a-methylated catecholamine analogs have been studied. In renal hypertensive rats, prolonged treatment with a-methyldopa, a-methyl-m-tyrosine, a-methyltyrosine or metaraminol produces dose-dependent decreases in blood pressure and dose-dependent depletion of myocardial catecholamines. The same order of relative activities was found in regard to noradrenaline depletion and antihypertensive effect, but there was no relationship between the degree of catecholamine depletion and the intensity of the hypotensive effect.
-
PeDtides A new series of peptides related to eledoisin, comprising acyl derivatives of 111, has been synthesized,with the object of obtaining long-acting hypotensive drugs. Some of these compounds, in particular R the butyryl and valeryl derivaI H-Lys-Phe-Ile-Gly-Leu-Met-NH2 tives, had a significantly longer duration of action than eledoiI11 sin .22 Both natural23 and synthetic2* forms of the decapeptide caerulein (IV) have been shown to lower blood pressure in the dog, rabbit, and in man. In the cat, the action of this substance is erratic and less intense, and in the rat it generally
IV
H-Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH~
causes a hypertensive or biphasic response. The duration of action, after i.v. injection in the dog, is considerably longer than for bradykinin or physalaemin. The threshold i.v. dose ranges between 0.01 and 0.1 pg/kg. 2 5 9
Lys -bradykinin (V) is more potent than bradykinin in lowering the mean systemic arterial blood pressure of the guinea pig, but less potent in other laboratory animals. LYE:' Kallidin (VI) is about as active as Kallidin in this regard. H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Lys-OH 1
2
3
4
5
6
7
8
H-Lys -Arg-Pro-Pro-Gly-Phe-Ser-Pro- Phe-Lys-OH 1
2
3
4
5
6
7
8
V
9
VI
9 1 0
6-Glycine-8-phenyllactic acid bradykinin (VII) has been synthesized and its biological activity studied. The vasodepressive effects in the rat and rabbit and the effects on
56 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
isolated rat uterus and capillary permeability in rabbit skin were respectively 4, 2, 0.5 and 0.04 times the potency of bradykinin. In the rat, three phases of action were observed: primary hypotension, Dartial restoration of the arterial blood H-Arg-Pro-Pro-Gly-Phe-Gly-Pro-PhLac-Arg-OH 1
2
3
4
5
6
7
8
VI I
S
gressure level, and second3Ty hypotension. Antibradykinin activity was not observed.
-
A n a vitro pharmacodynamic study was deDiazoxide signed to specify the t y p m of inhibition involved in the vascular action of diazoxide. The results indicate that diazoxide competes with barium for a soecific receptor site in the Vascular smooth muscle of the rat aorta. The location of this receptor is apparently closer to the process of muscle contraction than the a-adrenergic receptor, and may be a site normally activated by calcium. The specific competitive inhibition of barium-stimulated vasoconstriction by diazoxide may help to explain the mechanism by which diazoxide, arid possibly other benzothiadiazine antihypertensive agents, reduce blood pressure.28 From measurements of blood diazoxide levels in six adult human males at various times after i.v. drug administration, the half-life2gf diazoxide in blood was determined as 28 .o? 8 . 3 hr. Preliminary studies have indicated that a combination of diazoxide and furosemide may be of value in the treatment of the hypertensive uremic patient.30
-
Diuretics The antihypertensive properties of single doses of furosemide were evaluated in 113 patients and it was found that doses over 120 mg consistently produced a fall in arterial pressure, whereas smaller doses did not. The antihypertensive effect of high doses of furosemide did not seem to be related $9 the diuretic effect or to the decrease in plasma volume.
-
7-Azaindole-3-acetamidoxOther Antihypertensive Agents ime (71III)and indole-1-acetamidoxime (IX) exhibited antih Dertensive properties in the renal hypertensive rat and dog. 3%; 33 The EDs0 values for reduction of blood pressure to normotensive levels following oral administration to hypertensive rats were 14.2-k 3 . 1 and 18.2t4.5 mg/kg for V I I I and IX respectively. Oral administration of either V I I I or IX, once daily, to the hypertensive dog,produced gradual, sustained lowering of blood pressure without side effects. The maximum lowering of blood pressure occurred at three days. Neither compound lowered the
Chap. 6
Antihypertensives
Topli s s
57 -
blood pressure of the normotensive rat or dog. Additional studies suggest that the antihypertensive activity of VIII may be due to catecholamine release and depletion without the bretylium-like component of action seen with guanethidine. Some aspects of the effect of IX suggest catecholamine release and a-adrenergic blocking activity, but these properties do not appear sufficient to account for the antihypertensive pattern of action seen in the hypertensive dog. The antihypertensive properties of 1-(5-methyl-l-phenyl4-pyrazolyl)-~-~4-(~-tolyl)-piperazinyl]-l-~ropanone hydrochloride (XI) have been studied in animals. It produced a prolonged fall of blood pressure when administered i.v. or i.p. to anesthetized cats and dogs and lowered the blood pressure of renal hypertensive rats to normotensive levels. I .HC 1 The compound did not show C6Hf any ganglionic blocking X activity or marked interference with the transmission of impulses in the cervical sympathetic chain. A significant depletion of catecholamines occurred from rat heart and brain, and the compound was also shown to interfere with the uptake of noradrenaline by the rat heart. In addition, it produced marked peripheral vasodilation, possibly by acting on adrenergic @-receptors or by sensitizing these receptors to the action of adrenaline. Pharmacological investigations of 1-amino-bphenylpyridinium chloride (XI) have suggested&h32 the compound The compound may be a useful antihypertensive agent. ' depletes peripheral but not central stores of noradrenaline in the mouse and rat. The effects on the b l o o d CsH5 cl0 pressure of anesthetized animals are similar to those produced by guanethidine. However, in contrast to XI the latter compoundsit does not cause adrenergic blockade. Daily oral
a,,,
58 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
administration of XI in doses of 5 mg/kg to renal hypertensive dogs caused a pressor response on the first day (not seen if smaller initial doses were used), but on the second and third days there was a gradual reduction in the mean arterial blood 40 mm. mercury. The antihypertensive action pressure of 30 of the compound is probably related to its action on stores of catecholamine in sympathetic nerve endings.
-
A number of alkyl-substituted, mesoionic\J-oxatriazoles 0 (XII) were found t o produce, in anesthe-
/N-c-c-o 8I
tized dogs, a rapid, deep, and sustained hypotension with no observable side efThe potency followed a reverse fects .sf order of mesomeric contribution of the XI1 alkyl substituents. Molecular orbital calculations indicated a large positive character on NJ, which, when compared with the corresponding 3-alkylsydnone and 4acylsydnone nitrogen atom, seems t o correlate with hypotensive potency. R-PU'
k-0
Some 3-hydrazino-1,2-benzisothiazole 1,l-dioxides ( X I I I ) and various related hydrazones, carbamides, sulfamides, pyrazoles and pyrazolines have been synthesized and their hypotensive activities evaluated orally in the Goldblatt rat preparati~n.'~'~~ A large number of these had better than
x IV
XI11
NHN=CHC=CHCH~ I CH3
minimal activity, with some showing'a pronounced blood pressure lowering effect. One member of the series, 3-[2-(2-methyl2-butylidene)hydrazino]-l,2-benzisothiazole 1,l-dioxide (XIV), has undergone extensive pharmacological studies, which indicate that it probably has a mechanism of action other than blockade of the central or peripheral nervous systems.
-
The quinoline derivatives XV XVII were found to exhibit marked hypotensive activity in anesthetized rats and dogs, apparently b y mechanisms involving a-adrenergic blockade and direct musculotropic depression. In addition, it appears that XV and XVI lower blood pressure v i a a central mechanism. Based on data obtained in the anesthetized rat, XVI was the most potent of the three compounds."
Chap. 6
cH3m Antihypertensive s
RI
XV;
XVI;
Topli s s
59
R = - N = C H - C e H s ( 3 , bdiMe0) R = NH2
XVII; R = OH
CH3
2,6-Diamino-4-[2-(dimethylamino)ethoxy]pyrimidine (XVIII) produced a hypotensive response in anesthetized dogs, cats and rabbits, oCH2CH2N( CH3)2 and in unanesthetized neurogenic hypertensive, renal hypertensive, and normotensive dogs. The lowered blood pressure was ascribed to direct smooth muscle relaxation as H2N evidenced by a fall in peripheral resistance in the perfused dog hind XVIII limb and by relaxation of isolated vascular smooth muscle. This action is unrelated to occu ation or blockade of adrenergic or other types of receptors.4!2
GH2
Guancydine, 1-cyano-3-4-amylguanidine (XIX), exerted a hypotensive effect in renal hyperCH3NH tensive dogs, but not in neurogenic hypertensive or normotensive dogs, I II Repeated oral doses of 20 mg/kg CH3CHzCNHCNHCN over a 12 day period to metacortiI coid hypertensive rats brought about CH3 a reduction in both blood pressure x IX and cardiac hypertrophy. The hypotensive effect occurred by a mechanism other than a or 8-adrenergic blockade, adrenergic neurone blockade, ganglionic blockade or histamine liberation.43 Oral doses of guancydine in rats were found to Xsduce the pressor response to i.v. administered angiotensin.
-
General A double-blind study was conducted in which 40 patients with moderate or severe hypertension were treated with a-methyldopa, guanethidine, guanoxan and guanoclor. The last named drug had to be excluded from the trial because of severe side effects occurring after its administration. The results indicated that, where a satisfactory response is not obtained with diuretic therapy, the drug of choice to be added is a-methyldopa. When the latter does not have the desired effect, a sympatholytic agent is then given, and for this purpose the results showed that guanoxan has an advantage over gutmethidine.4 5
60 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
A study was conducted on the possible resetting of "barostats" in hypertensive patients, which suggests that in some patients the barostat may, in fact, be reset. It was further apparent that the initial level of pressure and extent of vascular complications are more important factors than the duration of high blood pressure in determining which patients fall into this group.*' References
.
H. Kcndig, H. Monnier, N. W. Levin, and R. W. Charlton, J ' , 1440 (1967) Arzneim. -Forsch., l 2. R. W. Sattler and P. A. van Zwieten, Europ. J. Pharmacol., 2 9 (1967). 3. E. Iisalo and S. Laurila, Current Therap. Rer;., 9, 358 1.
, ,
4.
5. 6. 7. 8. 9. 10. 11.
(1967)
J. G. Topliss in C . K. Cain,Ed., Ann. Rep. Med. Chem. 1966, Chap. 6, Academic Press, New York, 1967. J. Messerich, Med. Klin., 61, 2078 (1966). W. Lieb and K. Ridders, Arzeim.-Forsch., l6, 1610 (1966). J. BergstrBm, Er,. Bergquist-Poppen and H. Bucht, Arzneim.Forsch., 16, 1606 (1966). A. N. Brest, K. E. Kim, G. Onesti, J. L. Cangiano and C. D. Swartz, Circulation, 36, Suppl. 11, 76 (1967). G . M. Simpson, E. Kunz-Bartholini and T.P.S. Watts, J. Clin. Pharmacol., 1, 221 (1967). J. H. Short and T. B. Darby, J. Med. Chem., 10, 833 (1967). J. Bath, D. Pickering and R. Turner, Brit. Med. J., 4,
519 (1967)
S. G. Cotton and E. Montuschi, Brit. Med. J., 3, 174 (1967). 13 A. W. D. Leishman and G. Sandler, Angiology, 18, 705 (1967). 14. D. R. Varma, J. Pharm. Pharmacol., 19, 61 (19m). M. D. Day and M. J. Rand, J. Pharm. Pharmacol., 19, 395 15 (1967) 16. M. Henning and P. A. van Zwietin, J. Pharm. Pharmacol., 19, 405 (i967). 17. S. Cantor and A. J. Barnett, Lancet, 1, 625 (1967). 12. 9
200, 18. M. S. Belle and I. R. Mas, J. Amer. Mzd. ASSOC., goo (1967). 19 J. Weinreich and J. Rohr, Deutsch. Med. Wochschr., 92,
20. 21.
22. 23
161 (1967).
A. F. LoBuglio and J. H. Jandl., New Engl. J. Med., -' 276
658 (1967).
H. Brunner, P. R. Hedwall, L. Maitre and M. Meier, Brit. J. Pharmacol. Chemother , 30, (1967) L. Bernadi, R. deCastiglioK, G. B. Fregnan and A. H. Glasser, J. Pharm. Pharmacol., 19, 95 (1967). A. Anastasi, V. Erspamer and R.Fndean, Experientia,
23,
699 (1967)
.
.
Chap. 6
61 -
Topli s s
Antihypertensives
24. L. Bernadi, G. Bosisio, R. decastiglione and 0. Goffredo, Experientia, a,700 (1967).
V. Erspamer, G. Bertaccini, G. deCaro, R. Endean and M. Impicciatore, Experientia, 23, 702 (1967). 26. E. G. ErdSis, G. Can0 and H. Y. T. Yang, Biochem. Pharmacol., 25
27 * 28. 29
-
30 31 32
33 34
35 36 37 38
9
39 40. 41.
42.
r6, 1035 (1967).
G. A . Raudel, M. P. Filatova, L. A . Shchukina, T. S . Paskhina, M. S . Surovikina, S. S. Trapeznikova, and T. P. Egorova, J. Med. Chem., . 0 l , 242 (1967). A . J. Woh1,L. M. Hausler and F. E. Roth, J. Pharmacol. Exp. Ther., 158 531 (1967). S. Symchowicz, L. Winston, J. Black, M. Smith, B. Calesnick and I. I. A. Tabachnick, J. Pharm. Sci., 56 912 (1967). N. Kakaviatos, M. Davidov, L. Garvilovic F. A . Finnerty, Lancet, 1, 725 (1967). Jr M. Davidov, N. Kakaviatos and F. A. Finnerty, Jr., Circu125 (1967). lation, M. R. Bell, J. 0. Hoppe, H. E. Lape, D. Wood, A . Arnold and W. H. Selberis, Experientia, 3, 298 (1967). J. 0. Hoppe, H. E. Lape, A. Arnold and W. H. Selberis, 26, 459 (1967). Fed. Proc V. P. Arya, R. S. Grewal, J. David and C. L. Kaul, 514 (1967). Experientia, R. T. Brittain, J. B. Farmer, D. Jack L. E. Martin and A . C. Ritchie, Nature, 731 (1967j. V. A . Cullum, J. B. Farmer and S. L. Handley, Brit. J. Pharmacol. Chemother , s, 435 (1968) L. B. Kier, A . Al-Shamma, R. Hahn and A . Tye, J. Pharm. 55, 1467 (1966). Sci J. J. Traverso, C. W. Whitehead, J. F. Bell, H. E. Boaz and P. W. Willard, J. Med. Chem., 10, 840 (1967). C. W. Whitehead, J. J. Traverso, .F.J Bell and P. W. Willard, J. Med. Chem., 10, 844 (1967). P. W. Willard, C. W. Whitehead, J. F. Bell, H. E. Boaz J. Med. Chem., 10, 849 (1967). B. S . JandhyalaYG. J. Grega and 3 . P. Buckley, Arch. Int Pharmacodyn. Ther , 167, 217 (1967) S. J. Erreich, J. E. Heringslake, Jr., F. R. Warren, R. Jablonski, A. M. Helt, M. Sidelsky and R. E. Tedeschi, Fed. Proc , 26, 459 (1967) J. R. C u m m i n z and L. M. Lipchuck, Fed. Proc., 26, 459
.,
and
s, .,
a,
.
.
.,
.
.
. .
.
43 (1967). 44. A. N. Welter and J. L. Grace, Jr., Fed. Proc., 26, 460 (1967). 45 V. Vejlsgaard, M. Christensen and E. Clausen, Brit. Med. J., 2, 598 ( 1 9 6 7 ) . 46. R , H. Thurm and W. M. Smith, J. Amer. Med. Aasoc., 201, 85 ( 1 9 6 7 )
-
Section I1 Editor:
-
Pharmacodynamic Agents
Barry Bloom, Chas. Pfizer & Co., Chapter
Inc., Groton, Conn.
6. Antihypertensive Agents
John G. Topliss, Schering Corporation, Bloomfield, N. J.
-
Catapresan@ Additional papers have appeared in the clinical literature during 1967 on this new antihypertensive agent, but little came forth in the way of new devel- 7 opments concerning- mechanietic aspects of its action. N-1
i'
In one study in rats, evidence was obtained that at least part f the hypotensive action of Catsoresan6 (I) is due -t o a-adrenergic b1ockade.l The infusion I of low doses ( 0 . 2 5 2.0 Pg/kg) into the HC1 cerebral artery of anesthetized cats resulted in a considerable, dose-dependent decrease in blood pressure which developed suddenly,towards the end of the infusion. The same low doses, when given intravenously, had little effect on blood pressure. These results were viewed 88 consistent with a central mechanism of action of the drug. 2
-
An investigation in 21 patients3 produced overall results similar to those obtained previously by other investigators. 4 Wkth a daily dose of about 5007, there was an effective fall in systolic and diastolic blood pressure. Only a slight effect on orthostatic blood pressure was observed, and there was some slowing of the pulse rate. Sedation and dryness of the mouth were noted but were much reduced as the treatment progressed. The urinary excretion o f vanilmandelic acid, the main metabolite of catecholamines, was significantly reduced on the second day of drug administration,as compared to controls. This could have been due to interference with either the synthesis or the secretion of catecholamines. The authors spggested that this observation, coupled with the initial sedative effect and the disturbed sleep of some patients, may indicate a central effect. Another trial was conducted with 25 hypertensive patients over several weeks where the desired lowering of blood pressure was attained on the fourth day of treatment. Side effects were not troublesome.: Renal hypertension may even respond t o easurable degree. Parenteral adminietration of' Catapreea eaems to be eJfective and reliable in the treatment of hyperteneive crises. When combined with a thiazide for chronic administra-
w
54
Sect. I1
-
Pnarmacodynamic Agents
Bloom, Ed.
tion, the antihypertensive effect i s equivalent to thiazide plus a-methyldopa.' In a clinical pharmacologic trial with 12 chronic schizophrenic patients, no antipsychotic activity was observed.'
-
In a series of 25 derivatives of benzylGuanethidine Analogs guanidine, the most active compounds were p-trifluoromethylbenzylguanidine sulfate (11, R = H) and its a-methyl analog (11, R = CH3). NH Oral doses of 30 mg/kg of the former II initially increased, but subsequently pNHcNH2 decreased, blood pressure in both reR nal and neurogenic hypertensive dogs. Blood pressure was reduced for at I1 *1/2H~S04 least 5 0 hr, and the more marked reduction was observed with neurogenic hypertensive dogs. In the case of I1 (R = CH3), doses of 10, 5 and 2.5 mg/kg were employed, and a good dose-response relationship was apparent. Again,the neurogenic dogs exhibited a better response than did the renallo dogs. This compound was notable f o r its lack of side effects. Results of a study of 70 hypertensive patients treated with bethanidine for periods ranging from six months to two years have been reported. Satisfactory control of blood pressure was obtained in about three-quarters of the group, and side effects, apart fxpm postural hypotension (38$ of the patients), were rare. Liver-function test abnormalities have been noted among patients treated with guanoxan.12 The progress of 224 hypertensive patients treated with guanethidine for one to five and one-half years has been assessed .I3 a-Meth 1 Do a +a Related Compounds - It has been shown by Varma & that a-methyldopa produces its usual antihypertensive effect in immuno-sympathectomized rats made hypertensive by metacorticoid treatment. This observation was considered to be inconsistent with the hypothesis of Day and Rand that amethyldopa produces its antihypertensive effect by substituting a less active "false transmitter substance" for noradrenaline in the sympathetic nervous system. However, the latter authors have presented arguments to suggest that despite these findings the false transmitter hypothesis explainfgg the antihypertensive effect of a-methyldopa is still tenable. The proposal that a central effect might be the cause of the decrease of peripheral resistance brought about by amethyldopa is supported by evidence that a central$% mediated hypotensive effect may be demonstrated in the cat.
Chap. 6
Antihypertensives
55 -
Topli s s
A number of observations have been made on the occcrrence of positive Coombs tests and hemolytic anemia in patients receiving a-methyldopa.17-20 In this connection, the nature of the a-methyldopa red-cell antibody has been investigated .20
The antihypertensive2fffects of a-methylated catecholamine analogs have been studied. In renal hypertensive rats, prolonged treatment with a-methyldopa, a-methyl-m-tyrosine, a-methyltyrosine or metaraminol produces dose-dependent decreases in blood pressure and dose-dependent depletion of myocardial catecholamines. The same order of relative activities was found in regard to noradrenaline depletion and antihypertensive effect, but there was no relationship between the degree of catecholamine depletion and the intensity of the hypotensive effect.
-
PeDtides A new series of peptides related to eledoisin, comprising acyl derivatives of 111, has been synthesized,with the object of obtaining long-acting hypotensive drugs. Some of these compounds, in particular R the butyryl and valeryl derivaI H-Lys-Phe-Ile-Gly-Leu-Met-NH2 tives, had a significantly longer duration of action than eledoiI11 sin .22 Both natural23 and synthetic2* forms of the decapeptide caerulein (IV) have been shown to lower blood pressure in the dog, rabbit, and in man. In the cat, the action of this substance is erratic and less intense, and in the rat it generally
IV
H-Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH~
causes a hypertensive or biphasic response. The duration of action, after i.v. injection in the dog, is considerably longer than for bradykinin or physalaemin. The threshold i.v. dose ranges between 0.01 and 0.1 pg/kg. 2 5 9
Lys -bradykinin (V) is more potent than bradykinin in lowering the mean systemic arterial blood pressure of the guinea pig, but less potent in other laboratory animals. LYE:' Kallidin (VI) is about as active as Kallidin in this regard. H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Lys-OH 1
2
3
4
5
6
7
8
H-Lys -Arg-Pro-Pro-Gly-Phe-Ser-Pro- Phe-Lys-OH 1
2
3
4
5
6
7
8
V
9
VI
9 1 0
6-Glycine-8-phenyllactic acid bradykinin (VII) has been synthesized and its biological activity studied. The vasodepressive effects in the rat and rabbit and the effects on
56 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
isolated rat uterus and capillary permeability in rabbit skin were respectively 4, 2, 0.5 and 0.04 times the potency of bradykinin. In the rat, three phases of action were observed: primary hypotension, Dartial restoration of the arterial blood H-Arg-Pro-Pro-Gly-Phe-Gly-Pro-PhLac-Arg-OH 1
2
3
4
5
6
7
8
VI I
S
gressure level, and second3Ty hypotension. Antibradykinin activity was not observed.
-
A n a vitro pharmacodynamic study was deDiazoxide signed to specify the t y p m of inhibition involved in the vascular action of diazoxide. The results indicate that diazoxide competes with barium for a soecific receptor site in the Vascular smooth muscle of the rat aorta. The location of this receptor is apparently closer to the process of muscle contraction than the a-adrenergic receptor, and may be a site normally activated by calcium. The specific competitive inhibition of barium-stimulated vasoconstriction by diazoxide may help to explain the mechanism by which diazoxide, arid possibly other benzothiadiazine antihypertensive agents, reduce blood pressure.28 From measurements of blood diazoxide levels in six adult human males at various times after i.v. drug administration, the half-life2gf diazoxide in blood was determined as 28 .o? 8 . 3 hr. Preliminary studies have indicated that a combination of diazoxide and furosemide may be of value in the treatment of the hypertensive uremic patient.30
-
Diuretics The antihypertensive properties of single doses of furosemide were evaluated in 113 patients and it was found that doses over 120 mg consistently produced a fall in arterial pressure, whereas smaller doses did not. The antihypertensive effect of high doses of furosemide did not seem to be related $9 the diuretic effect or to the decrease in plasma volume.
-
7-Azaindole-3-acetamidoxOther Antihypertensive Agents ime (71III)and indole-1-acetamidoxime (IX) exhibited antih Dertensive properties in the renal hypertensive rat and dog. 3%; 33 The EDs0 values for reduction of blood pressure to normotensive levels following oral administration to hypertensive rats were 14.2-k 3 . 1 and 18.2t4.5 mg/kg for V I I I and IX respectively. Oral administration of either V I I I or IX, once daily, to the hypertensive dog,produced gradual, sustained lowering of blood pressure without side effects. The maximum lowering of blood pressure occurred at three days. Neither compound lowered the
Chap. 6
Antihypertensives
Topli s s
57 -
blood pressure of the normotensive rat or dog. Additional studies suggest that the antihypertensive activity of VIII may be due to catecholamine release and depletion without the bretylium-like component of action seen with guanethidine. Some aspects of the effect of IX suggest catecholamine release and a-adrenergic blocking activity, but these properties do not appear sufficient to account for the antihypertensive pattern of action seen in the hypertensive dog. The antihypertensive properties of 1-(5-methyl-l-phenyl4-pyrazolyl)-~-~4-(~-tolyl)-piperazinyl]-l-~ropanone hydrochloride (XI) have been studied in animals. It produced a prolonged fall of blood pressure when administered i.v. or i.p. to anesthetized cats and dogs and lowered the blood pressure of renal hypertensive rats to normotensive levels. I .HC 1 The compound did not show C6Hf any ganglionic blocking X activity or marked interference with the transmission of impulses in the cervical sympathetic chain. A significant depletion of catecholamines occurred from rat heart and brain, and the compound was also shown to interfere with the uptake of noradrenaline by the rat heart. In addition, it produced marked peripheral vasodilation, possibly by acting on adrenergic @-receptors or by sensitizing these receptors to the action of adrenaline. Pharmacological investigations of 1-amino-bphenylpyridinium chloride (XI) have suggested&h32 the compound The compound may be a useful antihypertensive agent. ' depletes peripheral but not central stores of noradrenaline in the mouse and rat. The effects on the b l o o d CsH5 cl0 pressure of anesthetized animals are similar to those produced by guanethidine. However, in contrast to XI the latter compoundsit does not cause adrenergic blockade. Daily oral
a,,,
58 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
administration of XI in doses of 5 mg/kg to renal hypertensive dogs caused a pressor response on the first day (not seen if smaller initial doses were used), but on the second and third days there was a gradual reduction in the mean arterial blood 40 mm. mercury. The antihypertensive action pressure of 30 of the compound is probably related to its action on stores of catecholamine in sympathetic nerve endings.
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A number of alkyl-substituted, mesoionic\J-oxatriazoles 0 (XII) were found t o produce, in anesthe-
/N-c-c-o 8I
tized dogs, a rapid, deep, and sustained hypotension with no observable side efThe potency followed a reverse fects .sf order of mesomeric contribution of the XI1 alkyl substituents. Molecular orbital calculations indicated a large positive character on NJ, which, when compared with the corresponding 3-alkylsydnone and 4acylsydnone nitrogen atom, seems t o correlate with hypotensive potency. R-PU'
k-0
Some 3-hydrazino-1,2-benzisothiazole 1,l-dioxides ( X I I I ) and various related hydrazones, carbamides, sulfamides, pyrazoles and pyrazolines have been synthesized and their hypotensive activities evaluated orally in the Goldblatt rat preparati~n.'~'~~ A large number of these had better than
x IV
XI11
NHN=CHC=CHCH~ I CH3
minimal activity, with some showing'a pronounced blood pressure lowering effect. One member of the series, 3-[2-(2-methyl2-butylidene)hydrazino]-l,2-benzisothiazole 1,l-dioxide (XIV), has undergone extensive pharmacological studies, which indicate that it probably has a mechanism of action other than blockade of the central or peripheral nervous systems.
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The quinoline derivatives XV XVII were found to exhibit marked hypotensive activity in anesthetized rats and dogs, apparently b y mechanisms involving a-adrenergic blockade and direct musculotropic depression. In addition, it appears that XV and XVI lower blood pressure v i a a central mechanism. Based on data obtained in the anesthetized rat, XVI was the most potent of the three compounds."
Chap. 6
cH3m Antihypertensive s
RI
XV;
XVI;
Topli s s
59
R = - N = C H - C e H s ( 3 , bdiMe0) R = NH2
XVII; R = OH
CH3
2,6-Diamino-4-[2-(dimethylamino)ethoxy]pyrimidine (XVIII) produced a hypotensive response in anesthetized dogs, cats and rabbits, oCH2CH2N( CH3)2 and in unanesthetized neurogenic hypertensive, renal hypertensive, and normotensive dogs. The lowered blood pressure was ascribed to direct smooth muscle relaxation as H2N evidenced by a fall in peripheral resistance in the perfused dog hind XVIII limb and by relaxation of isolated vascular smooth muscle. This action is unrelated to occu ation or blockade of adrenergic or other types of receptors.4!2
GH2
Guancydine, 1-cyano-3-4-amylguanidine (XIX), exerted a hypotensive effect in renal hyperCH3NH tensive dogs, but not in neurogenic hypertensive or normotensive dogs, I II Repeated oral doses of 20 mg/kg CH3CHzCNHCNHCN over a 12 day period to metacortiI coid hypertensive rats brought about CH3 a reduction in both blood pressure x IX and cardiac hypertrophy. The hypotensive effect occurred by a mechanism other than a or 8-adrenergic blockade, adrenergic neurone blockade, ganglionic blockade or histamine liberation.43 Oral doses of guancydine in rats were found to Xsduce the pressor response to i.v. administered angiotensin.
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General A double-blind study was conducted in which 40 patients with moderate or severe hypertension were treated with a-methyldopa, guanethidine, guanoxan and guanoclor. The last named drug had to be excluded from the trial because of severe side effects occurring after its administration. The results indicated that, where a satisfactory response is not obtained with diuretic therapy, the drug of choice to be added is a-methyldopa. When the latter does not have the desired effect, a sympatholytic agent is then given, and for this purpose the results showed that guanoxan has an advantage over gutmethidine.4 5
60 -
Sect. I1
-
Pharmacodynamic Agents
Bloom, Ed.
A study was conducted on the possible resetting of "barostats" in hypertensive patients, which suggests that in some patients the barostat may, in fact, be reset. It was further apparent that the initial level of pressure and extent of vascular complications are more important factors than the duration of high blood pressure in determining which patients fall into this group.*' References
.
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Chap. 6
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Antihypertensives
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